{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T14:24:15Z","timestamp":1788531855973,"version":"build-2803163510"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:p>This integrative review examines the neurobiological basis of addiction and neuromodulation-based treatment approaches in light of current literature, while proposing an integrative framework that extends beyond purely biological explanations. The neuroscience of addiction is addressed within Koob and Volkow\u2019s three-stage neurocircuit model (binge\/intoxication, withdrawal\/negative affect, and preoccupation\/craving), encompassing neuroadaptations in reward, stress, and executive control circuits, neuroimaging findings, genetic and epigenetic mechanisms, and neuromodulation-based treatment approaches. A central argument of this review is that addiction is not solely a brain circuit disorder but also a disorder of social connection and meaning: trauma, early adversity, insecure attachment, and social isolation constitute both neurobiological triggers and perpetuating factors of addiction, leaving epigenetic traces on reward and stress circuits that interact with genetic vulnerability. Genome-wide association studies emphasize polygenic risk architecture, while epigenetic mechanisms \u2014 particularly DNA methylation and histone modifications \u2014 translate environmental exposures into lasting neuroadaptations. Critically, the distinction between state and trait epigenetics must be carefully considered when interpreting cross-sectional findings, as longitudinal designs are required to establish translational clinical validity. Neuromodulation techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have demonstrated promising results in reducing craving and relapse risk; however, clinical application requires careful patient selection, standardized multi-session protocols, and integration with pharmacotherapy and psychotherapy. This review proposes a three-layer multidisciplinary treatment framework \u2014 biological, psychological, and social-relational \u2014 in which neuromodulation serves as one component of a comprehensive approach that targets the neurobiological, psychological, and relational dimensions of addiction simultaneously.<\/jats:p>","DOI":"10.3389\/fpsyt.2026.1887517","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:51:21Z","timestamp":1788529881000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond the brain circuit: a biopsychosocial integrative review of addiction neuroscience, epigenetic mechanisms, and multidisciplinary treatment"],"prefix":"10.3389","volume":"17","author":[{"given":"Yunus","family":"\u0130\u00e7er","sequence":"first","affiliation":[{"name":"Isparta Provincial Directorate of Youth and Sports, Ministry of Youth and Sports","place":["Isparta, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(16)00104-8","article-title":"Neurobiology of addiction: A neurocircuitry analysis","volume":"3","author":"Koob","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/GRF.0000000000000416","article-title":"Neurobiology of addiction","volume":"62","author":"Horseman","year":"2019","journal-title":"Clin Obstetrics Gynecology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.abrep.2023.100488","article-title":"Adverse childhood experiences and their association with substance use disorders in adulthood: A general population study (Young-HUNT)","volume":"17","author":"Broekhof","year":"2023","journal-title":"Addict Behav Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"991","DOI":"10.3390\/genes6040991","article-title":"Current and future prospects for epigenetic biomarkers of substance use disorders","volume":"6","author":"Andersen","year":"2015","journal-title":"Genes"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.5152\/ADDICTA.2021.21046","article-title":"Investigation of the relationship between the starting age of substance, alcohol, cigarette use, attachment styles, and temperament features of substance users","volume":"9","author":"Tuncay","year":"2022","journal-title":"Addicta: Turkish J Addict"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2024.1521016","article-title":"Opioidergic tuning of social attachment: reciprocal relationship between social deprivation and opioid abuse","volume":"18","author":"Galiza Soares","year":"2024","journal-title":"Front Neuroanat"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.847460","article-title":"The need for a new medical model: A challenge for biomedicine","volume":"196","author":"Engel","year":"1977","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci14121285","article-title":"The limbic system in co-occurring substance use and anxiety disorders: A narrative review using the RDoC framework","volume":"14","author":"Lin","year":"2024","journal-title":"Brain Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pscychresns.2025.111959","article-title":"Multiple dimensions approach in polysubstance use: An ESEM analysis based on the RDoC framework","volume":"348","author":"da Silva Pereira-Rufino","year":"2025","journal-title":"Psychiatry Research: Neuroimaging"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0173(93)90013-p","article-title":"The neural basis of drug craving: An incentive-sensitization theory of addiction","volume":"18","author":"Robinson","year":"1993","journal-title":"Brain Res Rev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2648.2005.03621.x","article-title":"The integrative review: Updated methodology","volume":"52","author":"Whittemore","year":"2005","journal-title":"J Advanced Nurs"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1177\/1534484316671606","article-title":"Writing integrative literature reviews: Using the past and present to explore the future","volume":"15","author":"Torraco","year":"2016","journal-title":"Hum Resource Dev Rev"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1037\/amp0000059","article-title":"Liking, wanting, and the incentive-sensitization theory of addiction","volume":"71","author":"Berridge","year":"2016","journal-title":"Am Psychol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev-psych-122414-033457","article-title":"Drug addiction: Updating actions to habits to compulsions ten years on","volume":"67","author":"Everitt","year":"2016","journal-title":"Annu Rev Psychol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/j.neuron.2018.03.048","article-title":"Neuroimaging impaired response inhibition and salience attribution in human drug addiction: A systematic review","volume":"98","author":"Zilverstand","year":"2018","journal-title":"Neuron"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291721000362","article-title":"Altered neural activities during response inhibition in adults with addiction: A voxel-wise meta-analysis","volume":"51","author":"Qiu","year":"2021","journal-title":"Psychol Med"},{"key":"B17","doi-asserted-by":"crossref","DOI":"10.1038\/s44220-024-00334-x","article-title":"Neuroimaging biomarkers in addiction","volume-title":"medRxiv","author":"Ekhtiari","year":"2024"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyab016","article-title":"Reward-related responses and tonic craving in cocaine addiction: An imaging study of the monetary incentive delay task","volume":"24","author":"Zhornitsky","year":"2021","journal-title":"Int J Neuropsychopharmacol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/adb.13200","article-title":"Shared network-level functional alterations across substance use disorders: A multi-level kernel density meta-analysis of resting-state functional connectivity studies","volume":"27","author":"Taebi","year":"2022","journal-title":"Addict Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.5152\/ADDICTA.2024.24076","article-title":"Brain reward system and its volumetric investigations in alcohol addiction","volume":"11","author":"Tabara","year":"2024","journal-title":"Addicta: Turkish J Addict"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.806685","article-title":"DNA epigenetics in addiction susceptibility","volume":"13","author":"Kaplan","year":"2022","journal-title":"Front Genet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32379","article-title":"The genetics of alcohol dependence: Twin and SNP-based heritability, and genome-wide association study based on AUDIT scores","volume":"168","author":"Mbarek","year":"2015","journal-title":"Am J Med Genet Part B Neuropsychiatr Genet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpsgos.2024.100375","article-title":"Alcohol use disorder-associated DNA methylation in the nucleus accumbens and dorsolateral prefrontal cortex","volume":"4","author":"White","year":"2024","journal-title":"Biol Psychiatry: Global Open Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.659","article-title":"Genome-wide association meta-analyses identify novel genetic risk loci and polygenic phenotype associations for heroin, methamphetamine and alcohol dependences","volume":"12","author":"Chang","year":"2022","journal-title":"Clin Transl Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291721000969","article-title":"Genetics of substance use disorders: A review","volume":"51","author":"Deak","year":"2021","journal-title":"Psychol Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1007\/s11920-019-1008-1","article-title":"Genetics of alcoholism","volume":"21","author":"Edenberg","year":"2019","journal-title":"Curr Psychiatry Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008222","article-title":"Solving the missing heritability problem","volume":"15","author":"Young","year":"2019","journal-title":"PloS Genet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI172882","article-title":"Considerations for the application of polygenic scores to clinical care of individuals with substance use disorders","volume":"134","author":"Kember","year":"2024","journal-title":"J Clin Invest"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1017\/S003329171500224X","article-title":"A novel sibling-based design to quantify genetic and shared environmental effects: Application to drug abuse, alcohol use disorder and criminal behavior","volume":"46","author":"Kendler","year":"2016","journal-title":"Psychol Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.20250909","article-title":"The promise of genetics in alcohol use disorders and the problems of phenotype, polygenetic architecture, ancestry, and comorbidity","volume":"182","author":"Ehlers","year":"2025","journal-title":"Am J Psychiatry"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0287446","article-title":"Candidate gene-environment interactions in substance abuse: A systematic review","volume":"18","author":"Jiang","year":"2023","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1556\/2006.2024.00029","article-title":"Gene\u2013environment interaction between gaming addiction and perceived stress in late adolescents and young adults: A twin study","volume":"13","author":"Hur","year":"2024","journal-title":"J Behav Addict"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/genes16121447","article-title":"Addiction susceptibility: Genetic factors, personality traits, and epigenetic interactions with the gut microbiome","volume":"16","author":"Borrego-Ruiz","year":"2025","journal-title":"Genes"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/ajad.12465","article-title":"DNA methylation and alcohol use disorders: Progress and challenges","volume":"26","author":"Zhang","year":"2017","journal-title":"Am J Addict"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1177\/00912174231195751","article-title":"Adverse childhood experiences and early initiation of substance use: A survival analysis","volume":"59","author":"Meadows","year":"2024","journal-title":"Int J Psychiatry Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2022.964671","article-title":"Human connection as a treatment for addiction","volume":"13","author":"Clements","year":"2022","journal-title":"Front Psychol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/s13148-021-01202-6","article-title":"Longitudinal DNA methylation dynamics as a practical indicator in clinical epigenetics","volume":"13","author":"Komaki","year":"2021","journal-title":"Clin Epigenet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.828055","article-title":"Epigenetic effects of addictive drugs in the nucleus accumbens","volume":"15","author":"Anderson","year":"2022","journal-title":"Front Mol Neurosci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e16407","article-title":"Histone modifications in cocaine, methamphetamine and opioids","volume":"9","author":"Cheng","year":"2023","journal-title":"Heliyon"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.984997","article-title":"Epigenetic mechanisms involved in methamphetamine addiction","volume":"13","author":"Wang","year":"2022","journal-title":"Front Pharmacol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/s42003-026-09705-9","article-title":"Addictive drug abuse and depression\u2014a focus on epigenetics","volume":"9","author":"Zhang","year":"2026","journal-title":"Commun Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s44220-024-00277-3","article-title":"Shared genetics of ADHD, cannabis use disorder and cannabis use and prediction of cannabis use disorder in ADHD","volume":"2","author":"Nielsen","year":"2024","journal-title":"Nat Ment Health"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-024-02547-z","article-title":"The genetic landscape of substance use disorders","volume":"29","author":"Gerring","year":"2024","journal-title":"Mol Psychiatry"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1177\/00048674211054740","article-title":"Comorbidity between mood and substance-related disorders: A systematic review and meta-analysis","volume":"56","author":"Saha","year":"2022","journal-title":"Aust New Z J Psychiatry"},{"key":"B45","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1186\/s40359-025-02917-4","article-title":"A study on the effects of addiction level, stress, and social support of drug relapse patients on changes in motivation of quitting substance misuse behaviors","volume":"13","author":"Liu","year":"2025","journal-title":"BMC Psychol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-023-01776-0","article-title":"A systematic review and meta-analysis of neuromodulation therapies for substance use disorders","volume":"49","author":"Mehta","year":"2024","journal-title":"Neuropsychopharmacology"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.5152\/ADDICTA.2024.24213","article-title":"Transcranial magnetic stimulation in alcohol use disorder treatment: A narrative review","volume":"11","author":"Uygur","year":"2024","journal-title":"Addicta: Turkish J Addict"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.addbeh.2020.106760","article-title":"Transcranial magnetic stimulation: A review about its efficacy in the treatment of alcohol, tobacco and cocaine addiction","volume":"114","author":"Antonelli","year":"2021","journal-title":"Addict Behav"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1097\/YCT.0000000000000401","article-title":"Transcranial direct current stimulation in substance use disorders: A systematic review of scientific literature","volume":"33","author":"Lupi","year":"2017","journal-title":"J ECT"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/ajad.13517","article-title":"Systematic review and meta-analysis: Combining transcranial magnetic stimulation or direct current stimulation with pharmacotherapy for treatment of substance use disorders","volume":"33","author":"Bormann","year":"2024","journal-title":"Am J Addict"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3171\/2018.5.FOCUS18163","article-title":"Deep brain stimulation for the treatment of drug addiction","volume":"45","author":"Wang","year":"2018","journal-title":"Neurosurgical Focus"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-022-01229-4","article-title":"Deep brain stimulation for addictive disorders \u2014 Where are we now","volume":"19","author":"Yuen","year":"2022","journal-title":"Neurotherapeutics"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12152-017-9310-2","article-title":"Introduction: Testing and refining Marc Lewis's critique of the brain disease model of addiction","volume":"10","author":"Snoek","year":"2017","journal-title":"Neuroethics"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1177\/1745691611400243","article-title":"Received wisdom regarding the roles of craving and dopamine in addiction: A response to Lewis's critique of addiction: A disorder of choice","volume":"6","author":"Heyman","year":"2011","journal-title":"Perspect psychol Sci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.7334\/psicothema2017.303","article-title":"Brain disease or biopsychosocial model in addiction? Remembering the Vietnam veteran study","volume":"30","author":"Beco\u00f1a","year":"2018","journal-title":"Psicothema"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2024.1352818","article-title":"Recovery-supportive interventions for people with substance use disorders: a scoping review","volume":"15","author":"Sinclair","year":"2024","journal-title":"Front Psychiatry"},{"key":"B57","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1080\/10550887.2024.2440184","article-title":"Neurobiology, psychotherapeutic interventions, and emerging therapies in addiction: A systematic review","volume":"44","author":"Lomas","year":"2026","journal-title":"J Addictive Dis"},{"key":"B58","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/S2215-0366(23)00095-0","article-title":"Buprenorphine versus methadone for the treatment of opioid dependence: A systematic review and meta-analysis of randomised and observational studies","volume":"10","author":"Degenhardt","year":"2023","journal-title":"Lancet Psychiatry"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.11363","article-title":"Comparative effectiveness associated with buprenorphine and naltrexone in opioid use disorder and cooccurring polysubstance use","volume":"5","author":"Xu","year":"2022","journal-title":"JAMA Netw Open"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.19761","article-title":"Pharmacotherapy for alcohol use disorder: A systematic review and meta-analysis","volume":"330","author":"McPheeters","year":"2023","journal-title":"JAMA"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1111\/adb.70035","article-title":"Effectiveness of disulfiram as adjunct to addiction-focused treatment for persons with severe alcohol use disorder","volume":"30","author":"Schallenberg","year":"2025","journal-title":"Addict Biol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1097\/CRD.0000000000001171","article-title":"Emerging and established pharmacotherapies for smoking cessation: A review","author":"Huhulea","year":"2026","journal-title":"Cardiol Rev"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1080\/15504263.2023.2293854","article-title":"Integrative pharmacology in the treatment of substance use disorders","volume":"20","author":"Donlon","year":"2024","journal-title":"J Dual Diagnosis"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.22010071","article-title":"Project Harmony: A meta-analysis with individual patient data on behavioral and pharmacologic trials for comorbid posttraumatic stress and alcohol or other drug use disorders","volume":"180","author":"Hien","year":"2023","journal-title":"Am J Psychiatry"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1515\/jom-2021-0163","article-title":"Review of medication-assisted treatment for opioid use disorder","volume":"122","author":"Ghanem","year":"2022","journal-title":"J Osteopathic Med"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2023.115318","article-title":"Meta-review on the efficacy of psychological therapies for the treatment of substance use disorders","volume":"326","author":"Dellazizzo","year":"2023","journal-title":"Psychiatry Res"},{"key":"B67","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1186\/s12888-023-05413-4","article-title":"Effects of brief cognitive behavioral therapy on mental health in substance-related disorder: A randomized controlled trial","volume":"23","author":"Alavi","year":"2023","journal-title":"BMC Psychiatry"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1002\/capr.70083","article-title":"Developing a counselling and psychotherapy competency framework for addictions: A systematic review","volume":"26","author":"Mahmood","year":"2026","journal-title":"Counselling Psychother Res"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.34172\/ahj.2023.1434","article-title":"Prediction of addiction relapse based on perceived social support and childhood trauma","volume":"15","author":"Arabshahi","year":"2023","journal-title":"Addict Health"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2026.1780192","article-title":"A comparative interventional study on the effectiveness of acceptance and commitment therapy, emotion-focused therapy, and attachment-based therapy in improving emotion regulation among adolescents with digital game addiction","volume":"17","author":"G\u00fcng\u00f6r","year":"2026","journal-title":"Front Psychol"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1887517\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:51:23Z","timestamp":1788529883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1887517\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":70,"alternative-id":["10.3389\/fpsyt.2026.1887517"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2026.1887517","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]},"article-number":"1887517"}}