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Heroin Addiction and Related Clinical Problems: 2025, 27, 21

Cognitive functioning in subjects with Substance Use Disorder: retrospective observational study on the transition from Methadone to Levomethadone

Silvia Pinna, Giuseppe Gagliardo, Selene Regio, Francesca Pagliari, Lorenzo Finocchiaro, Maria Cristina Marrone, and Pietro Casella

Digital Object Identifier:
https://doi.org/10.62401/2531-4122-2025-21

Summary: Background: Opioid Use Disorder (OUD) is frequently accompanied by cognitive impairments that may hinder treatment adherence and relapse prevention. Methadone Maintenance Treatment (MMT), the standard form of Opioid Agonist Therapy (OAT), has shown inconsistent effects on cognition, particularly in executive function and working memory. Levomethadone, the R-enantiomer of racemic methadone, displays higher μ-opioid receptor affinity and equivalent clinical efficacy at approximately half the dose. Preliminary evidence suggests it may offer improved tolerability and cognitive outcomes, though systematic data remain scarce. Methods: This retrospective observational study compared cognitive performance and quality of life (QoL) in OUD patients receiving OAT. Assessments were conducted at baseline (T0, during MMT) and after six months (T1), using the Inverted Motor Learning Test (IMLT), Trail Making Test (TMT-A/B), Digit Span (Forward/Backward), and Phonemic Verbal Fluency (PVF), with QoL evaluated via the Substance Use Recovery Evaluator (SURE). Patients were divided into a control group continuing MMT (n=17) and an experimental group transitioned to levomethadone (n=23). Results: The experimental group showed significant improvements in IMLT (T1: 3.59±1.0 vs. T0: 1.50±0.7, p < 0.0001) and Digit Span Forward (T1: 3.00±1.6 vs. T0: 2.39±1.8, p = 0.038), indicating gains in motor learning and working memory. Minor enhancements in PVF and QoL were also observed. In contrast, the control group exhibited stable or slightly declining performance. Correlation analyses suggested a stronger link between cognitive improvements and QoL in the levomethadone group. Conclusions: These findings support levomethadone as a potentially advantageous OAT alternative, warranting further investigation to elucidate its long-term cognitive and clinical benefits.

Keywords: Cognitive Functioning; Opioid Agonist Therapy (OAT); Methadone; Levomethadone; Substance Use Disorder (SUD).