Modulatory Effects of Methadone on Brain Network Instability in Metham-phetamine Use; A Cross-sectional Study

Abstract

Introduction: While methadone maintenance therapy (MMT) is well established in opioid use disorder, its potential modulatory effects on brain network dynamics in methamphetamine use disorder (MUD) remain unclear. This study aimed to evaluate the association of MMT with normalization of disrupted brain network activity in MUD. Methods: In this cross-sectional study, resting-state functional magnetic resonance imaging (MRI) data were obtained from healthy controls, untreated methamphetamine users, and methamphetamine users receiving MMT who also met diagnostic criteria for opioid use disorder and were enrolled in supervised MMT programs. Dynamic functional connectivity was assessed using dynamic independent component analysis within the CONN toolbox. Clinical status was evaluated using the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS). Group comparisons were performed using general linear models controlling for age, education level, duration of methamphetamine use, and head-motion parameters. Results: 110 participants (35 healthy controls, 45 untreated individuals with methamphetamine use, and 30 individuals with methamphetamine use receiving MMT) were studied. Cognitive performance assessed using BACS differed significantly across groups (p = 0.002, eta(2) = 0.332), with untreated methamphetamine users demonstrating the lowest scores (19.88 +/- 6.20), healthy controls the highest scores (30.38 +/- 5.85), and MMT-treated participants showing intermediate performance (22.48 +/- 7.61). Compared with untreated methamphetamine users, MMT-treated participants showed higher BACS scores, although the methamphetamine versus MMT effect was small-to-moderate (Cohen's d =-0.38, 95 confidence interval (CI):-0.85 to 0.08). PANSS positive, negative, and general psychopathology scores differed significantly across groups (all p < 0.001), with large effect sizes (eta(2) range = 0.802-0.913). Untreated methamphetamine users exhibited the greatest symptom severity (Cohen's d = 2.74, 95 CI: 2.10-3.38), whereas MMT-treated participants showed lower symptom burden than untreated users (Cohen's d = 2.26, 95 CI: 1.67-2.85), although scores remained elevated relative to healthy controls (d = 4.22, 95 CI: 3.34, 5.11). The methamphetamine versus MMT effect sizes were large for PANSS positive (Cohen's d = 2.74, 95 CI: 2.10-3.38), PANSS negative (Cohen's d = 2.26, 95 CI: 1.67-2.85), and PANSS general psychopathology (Cohen's d = 1.64, 95 CI: 1.11-2.18). Conclusion: Methamphetamine use is associated with disrupted and unstable brain network dynamics that may underlie acute neurobehavioral disturbances seen in emergency settings. MMT was associated with partial stabilization of these alterations, suggesting a potential neurobiological benefit beyond opioid substitution. Persistent network abnormalities, however, indicate the need for adjunctive therapeutic strategies. Dynamic connectivity measures may offer a novel biomarker for risk stratification and management of substance-related emergencies.