{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T04:50:56Z","timestamp":1766724656478,"version":"3.48.0"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Emotional dysregulation and impulsivity represent key risk factors for adverse trajectories in adults with ADHD and are frequently observed among patients with opioid use disorder (OUD). Levomethadone, the R-enantiomer of methadone, provides more stable dopaminergic modulation than the racemic formulation and may improve emotional control. The primary objective was to examine emotional, clinical, and substance use changes after the switch to levomethadone and to determine whether these trajectories differed according to ADHD screening status. This study evaluated emotional, clinical, and behavioral outcomes\u2014including substance use\u2014after transitioning from racemic methadone to levomethadone maintenance therapy, focusing on the moderating role of ADHD symptoms and dose escalation. Methods: Eighty-three OUD patients in methadone maintenance were assessed at baseline, T1 (mean = 2.13 months, SD = 0.65), and T2 (mean = 6.20 months, SD = 0.91). Emotional dysregulation (RIPOST), clinical severity (Clinical Global Impression), and days of substance use were analyzed using Linear Mixed Models (participants with \u22651 valid follow-up). ADHD symptoms (Adult ADHD Self-Report Scale DSM-5) were evaluated with Wilcoxon signed-rank tests. Dose escalation (\u2191levomethadone) was defined as \u22651 increase during follow-up and was only included in the mixed models. Substance use analyses were restricted to baseline active users. Results: Emotional impulsivity significantly decreased over time only in participants screening positive for ADHD symptoms (ASRS \u2265 14), independent of dose escalation. Emotional instability also declined but across the full cohort. CGI scores improved in all participants. Substance use patterns showed a modest overall improvement, with reductions most evident for sedatives and alcohol. The findings indicate a specific effect of levomethadone on affective regulation and clinical stabilization, particularly in individuals with impulsivity traits. Conclusions: Levomethadone maintenance appears to improve emotional regulation and global functioning beyond dose-related effects, supporting its potential value in complex OUD patients with clinically relevant ADHD symptomatology. Combined treatment with levomethadone and methylphenidate may further enhance executive control and craving regulation in this population.<\/jats:p>","DOI":"10.3390\/jcm15010089","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T03:06:02Z","timestamp":1766718362000},"page":"89","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Levomethadone Selectively Reduces Emotional Impulsivity in ASRS-Positive ADHD\u2013OUD Patients, Independent of Dose Escalation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7281-1337","authenticated-orcid":false,"given":"Alessandro","family":"Pallucchini","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Addictions, Section of Addictions, North-Western Tuscany Local Health Unit, Tuscany NHS, Apuan Zone, Via Carriona, 241\/B, 54033 Carrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Varese","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Addictions, Section of Addictions, North-Western Tuscany Local Health Unit, Tuscany NHS, Apuan Zone, Via Carriona, 241\/B, 54033 Carrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Pergentini","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Addictions, Section of Addictions, North-Western Tuscany Local Health Unit, Tuscany NHS, Lucca Zone, Cittadella della Salute \u201cOspedale Campo di Marte\u201d, 55100 Lucca, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Cerrai","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Addictions, Section of Addictions, North-Western Tuscany Local Health Unit, Tuscany NHS, Lucca Zone, Cittadella della Salute \u201cOspedale Campo di Marte\u201d, 55100 Lucca, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8022-7624","authenticated-orcid":false,"given":"Samuele","family":"Gemignani","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Addictions, Section of Addictions, North-Western Tuscany Local Health Unit, Tuscany NHS, Apuan Zone, Via Carriona, 241\/B, 54033 Carrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Parapetto","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Addictions, Section of Addictions, North-Western Tuscany Local Health Unit, Tuscany NHS, Livorno Zone, Via Tiberio Scali, 11, 57121 Livorno, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2179-1297","authenticated-orcid":false,"given":"Francesco","family":"Simonetti","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Addictions, Section of Addictions, North-Western Tuscany Local Health Unit, Tuscany NHS, Viareggio Zone, Via della Gronda, 15, 55049 Viareggio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-0576","authenticated-orcid":false,"given":"Icro","family":"Maremmani","sequence":"additional","affiliation":[{"name":"VP Dole Research Group, G. De Lisio Institute of Behavioral Sciences, Via di Pratale 3, 56121 Pisa, Italy"},{"name":"Department of Medicine, Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro 8, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7728-3705","authenticated-orcid":false,"given":"Angelo G. I.","family":"Maremmani","sequence":"additional","affiliation":[{"name":"VP Dole Research Group, G. De Lisio Institute of Behavioral Sciences, Via di Pratale 3, 56121 Pisa, Italy"},{"name":"Department of Medicine, Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro 8, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41380-025-03178-8","article-title":"Prevalence of attention deficit hyperactivity disorder\/hyperkinetic disorder of pediatric and adult populations in clinical settings: A systematic review, meta-analysis and meta-regression","volume":"31","author":"Johnson","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rohner, H., Gaspar, N., Philipsen, A., and Schulze, M. (2023). Prevalence of Attention Deficit Hyperactivity Disorder (ADHD) among Substance Use Disorder (SUD) Populations: Meta-Analysis. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20021275"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1159\/000484240","article-title":"Attention Deficit Hyperactivity Disorder Symptoms are Common in Patients in Opioid Maintenance Treatment","volume":"23","author":"Abel","year":"2017","journal-title":"Eur. Addict. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.7189\/jogh.11.04009","article-title":"The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis","volume":"11","author":"Song","year":"2021","journal-title":"J. Glob. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1111\/add.12086","article-title":"Attention deficit hyperactivity disorder (ADHD) among illicit psychostimulant users: A hidden disorder?","volume":"108","author":"Kaye","year":"2013","journal-title":"Addiction"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.cpr.2011.01.006","article-title":"Prospective association of childhood attention-deficit\/hyperactivity disorder (ADHD) and substance use and abuse\/dependence: A meta-analytic review","volume":"31","author":"Lee","year":"2011","journal-title":"Clin. Psychol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1037\/0021-843X.112.3.497","article-title":"Childhood predictors of adolescent substance use in a longitudinal study of children with ADHD","volume":"112","author":"Molina","year":"2003","journal-title":"J. Abnorm. Psychol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jaac.2010.09.019","article-title":"Childhood attention-deficit\/hyperactivity disorder and future substance use disorders: Comparative meta-analyses","volume":"50","author":"Charach","year":"2011","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"ref_9","unstructured":"Barkley, R.A. (2022). Treating ADHD in Children and Adolescents-What Every Clinician Needs to Know, Guilford Publications."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/ajad.12500","article-title":"Neuroimaging the neural correlates of increased risk for substance use disorders in attention-deficit\/hyperactivity disorder-A systematic review","volume":"26","author":"Adisetiyo","year":"2017","journal-title":"Am. J. Addict."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12954-024-01079-7","article-title":"ADHD: Prevalence and effect on opioid use disorder treatment outcome in a French sample of patients receiving medication for opioid use disorder\u2014The influence of impulsivity as a mediating factor","volume":"21","author":"Beslot","year":"2024","journal-title":"Harm Reduct. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40479-023-00235-y","article-title":"Identifying different patterns of emotion dysregulation in adult ADHD","volume":"10","author":"Martz","year":"2023","journal-title":"Borderline Pers. Disord. Emot. Dysregulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.neubiorev.2007.11.003","article-title":"Impulsivity as a vulnerability marker for substance-use disorders: Review of findings from high-risk research, problem gamblers and genetic association studies","volume":"32","author":"Lawrence","year":"2008","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pallucchini, A., Carli, M., Maremmani, A.G.I., Scarselli, M., Perugi, G., and Maremmani, I. (2021). Influence of Substance Use Disorder on Treatment Retention of Adult-Attention-Deficit\/Hyperactive Disorder Patients. A 5-Year Follow-Up Study. J. Clin. Med., 10.","DOI":"10.3390\/jcm10091984"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1172\/JCI126912","article-title":"Opioid\u2013galanin receptor heteromers mediate the dopaminergic effects of opioids","volume":"129","author":"Cai","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1124\/pr.111.004598","article-title":"Functional selectivity at the \u03bc-opioid receptor: Implications for understanding opioid analgesia and tolerance","volume":"63","author":"Raehal","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1046\/j.1440-1681.1999.03049.x","article-title":"Opioid receptor signalling mechanisms","volume":"26","author":"Connor","year":"1999","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.biopsych.2019.05.023","article-title":"Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement","volume":"87","author":"Koob","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1038\/s41380-024-02864-3","article-title":"Reply to \u201cLetter to the Editor regarding \u2018Unique pharmacodynamic properties and low abuse liability of the \u03bc-opioid receptor ligand (S)-methadone\u2019\u201d","volume":"30","author":"Levinstein","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"MacDonald, H.J., Kleppe, R., Szigetvari, P.D., and Haavik, J. (2024). The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1492126"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s44192-022-00030-1","article-title":"An overview on neurobiology and therapeutics of attention-deficit\/hyperactivity disorder","volume":"3","author":"Grevet","year":"2023","journal-title":"Discov. Ment. Health"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41583-024-00869-z","article-title":"Neurobiology of attention-deficit hyperactivity disorder: Historical challenges and emerging frontiers","volume":"25","author":"Koirala","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1176\/appi.ajp.2013.13070966","article-title":"Emotion dysregulation in attention deficit hyperactivity disorder","volume":"171","author":"Shaw","year":"2014","journal-title":"Am. J. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ejphar.2007.09.042","article-title":"PET imaging of dopamine transporter and drug craving during methadone maintenance treatment and after prolonged abstinence in heroin users","volume":"579","author":"Shi","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jsat.2018.05.004","article-title":"The association between impulsivity, emotion regulation, and symptoms of alcohol use disorder","volume":"91","author":"Jakubczyk","year":"2018","journal-title":"J. Subst. Abus. Treat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/s41398-024-03159-5","article-title":"Re-evaluating our focus in addiction: Emotional dysregulation is a critical driver of relapse to drug use","volume":"14","author":"Hand","year":"2024","journal-title":"Transl. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/add.16001","article-title":"Emotion regulation in substance use disorders: A systematic review and meta-analysis","volume":"118","author":"Stellern","year":"2023","journal-title":"Addiction"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/s13643-021-01764-9","article-title":"Retention in opioid agonist treatment: A rapid review and meta-analysis comparing observational studies and randomized controlled trials","volume":"10","author":"Klimas","year":"2021","journal-title":"Syst. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"O\u2019Connor, A.M., Cousins, G., Durand, L., Barry, J., and Boland, F. (2020). Retention of patients in opioid substitution treatment: A systematic review. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232086"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1177\/10870547241312575","article-title":"Assessing the Construct Validity of the Adult ADHD Self-report Scale for DSM-5 and Prevalence of ADHD in a Danish Population Sample","volume":"29","author":"Christensen","year":"2025","journal-title":"J. Atten. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.jad.2019.07.028","article-title":"Reactivity, Intensity, Polarity and Stability questionnaire (RIPoSt-40) assessing emotional dysregulation: Development, reliability and validity","volume":"257","author":"Brancati","year":"2019","journal-title":"J. Affect. Disord."},{"key":"ref_32","first-page":"28","article-title":"The clinical global impressions scale: Applying a research tool in clinical practice","volume":"4","author":"Busner","year":"2007","journal-title":"Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Monsalves, M.J., Bangdiwala, A.S., Thabane, A., and Bangdiwala, S.I. (2020). LEVEL (Logical Explanations & Visualizations of Estimates in Linear mixed models): Recommendations for reporting multilevel data and analyses. BMC Med. Res. Methodol., 20.","DOI":"10.1186\/s12874-019-0876-8"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e12286","DOI":"10.1002\/trc2.12286","article-title":"Proportional constrained longitudinal data analysis models for clinical trials in sporadic Alzheimer\u2019s disease","volume":"8","author":"Wang","year":"2022","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/s41380-023-02353-z","article-title":"Unique pharmacodynamic properties and low abuse liability of the \u00b5-opioid receptor ligand (S)-methadone","volume":"29","author":"Levinstein","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1523\/JNEUROSCI.12-02-00483.1992","article-title":"Opioids excite dopamine neurons by hyperpolarization of local interneurons","volume":"12","author":"Johnson","year":"1992","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1038\/sj.npp.1300889","article-title":"Profile of executive and memory function associated with amphetamine and opiate dependence","volume":"31","author":"Ersche","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.drugalcdep.2005.04.007","article-title":"The effects of racemic d,l-methadone and l-methadone in substituted patients\u2014A randomized controlled study","volume":"80","author":"Verthein","year":"2005","journal-title":"Drug Alcohol Depend."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12954-016-0095-0","article-title":"Opioid tolerance in methadone maintenance treatment: Comparison of methadone and levomethadone in long-term treatment","volume":"13","author":"Gutwinski","year":"2016","journal-title":"Harm Reduct. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1037\/0021-843X.116.2.362","article-title":"Stress-response-dampening effects of alcohol: Attention as a mediator and moderator","volume":"116","author":"Sher","year":"2007","journal-title":"J. Abnorm. Psychol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.brat.2016.06.005","article-title":"The effects of alcohol on emotion in social drinkers","volume":"88","author":"Sayette","year":"2017","journal-title":"Behav. Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1037\/0022-3514.69.5.990","article-title":"Drinking to regulate positive and negative emotions: A motivational model of alcohol use","volume":"69","author":"Cooper","year":"1995","journal-title":"J. Pers. Soc. Psychol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s00213-021-05802-1","article-title":"The acute effects of alcohol on state rumination in the laboratory","volume":"238","author":"Mollaahmetoglu","year":"2021","journal-title":"Psychopharmacology"},{"key":"ref_44","first-page":"e40969","article-title":"Cannabis Use in Patients with Attention Deficit Hyperactivity Disorder: A Systematic Review","volume":"15","author":"Dhamija","year":"2023","journal-title":"Cureus"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.jpsychires.2022.11.029","article-title":"Cannabis use in Attention\u2014Deficit\/Hyperactivity Disorder (ADHD): A scoping review","volume":"157","author":"Francisco","year":"2023","journal-title":"J. Psychiatr. Res."},{"key":"ref_46","unstructured":"Preedy, V. (2017). Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment, Elsevier."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/acer.13272","article-title":"Clinical Validation of Reduced Alcohol Consumption After Treatment for Alcohol Dependence Using the World Health Organization Risk Drinking Levels","volume":"41","author":"Witkiewitz","year":"2017","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"107648","DOI":"10.1016\/j.drugalcdep.2019.107648","article-title":"Clinical validation of reduction in cocaine frequency level as an endpoint in clinical trials for cocaine use disorder","volume":"205","author":"Roos","year":"2019","journal-title":"Drug Alcohol Depend."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/89\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T03:26:09Z","timestamp":1766719569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/89"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["jcm15010089"],"URL":"https:\/\/doi.org\/10.3390\/jcm15010089","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]}}}