Baclofen Modulates Neural Intrinsic Functional Connectivity in Treatment-Seeking Individuals With Alcohol Use Disorder.

BACKGROUND

Chronic alcohol use alters brain networks related to reward and stress regulation, contributing to alcohol use disorder (AUD). Baclofen, a GABAB receptor agonist, reduces cue-elicited neural responses and alcohol consumption, but its effects on intrinsic functional connectivity remain unclear. This study investigates the dose-specific effects of baclofen on intrinsic resting-state functional connectivity in treatment-seeking individuals with AUD.

METHODS

In this double-blind, placebo-controlled, randomized clinical trial, 29 participants with AUD were randomized to receive placebo (n = 10), low-dose baclofen (30 mg/day, n = 10), or high-dose baclofen (75 mg/day, n = 9) for 12 weeks. Resting-state fMRI data were collected at rest during week 2. A data-driven parcellation approach assessed connectivity patterns across the brain and associations with percentage of heavy drinking days and percentage of days abstinent post scan were examined in an exploratory analysis.

RESULTS

Compared to placebo, high-dose baclofen was associated with significant differences in intrinsic connectivity in brain regions linked with reward, stress, attentional, and salience networks. Higher connectivity was observed between the somatomotor network and regions involved in stress regulation (e.g., hypothalamus) and reward processing, while lower connectivity was observed within salience and attentional networks. These changes were not observed in the low-dose or placebo groups. Although nonsignificant, associations between MES and clinical outcomes demonstrated moderate, directionally consistent effects for abstinence-related outcomes.

CONCLUSIONS

High-dose baclofen may modulate intrinsic brain connectivity in key networks implicated in AUD, including systems involved in attention and stress regulation. Although statistically significant relationships between functional connectivity and clinical outcomes were not identified, trends suggest that connectivity differences between high-dose baclofen and placebo may be relevant to treatment response. These neurobiological findings provide additional support for baclofen as a dose-dependent pharmacotherapy for AUD and highlight the need for larger samples to clarify the relationship between intrinsic connectivity and clinical outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT01711125 letter of completion.