Baclofen at the Crossroads: Pharmacological Ambivalence in Multiple Sclerosis and Alcohol Use Disorder

Background/Objectives: Baclofen, a GABAB receptor agonist, has been a cornerstone in the management of spasticity in multiple sclerosis (MS) for decades, and its repositioning at high doses for alcohol use disorder (AUD) has generated clinical and ethical debate. This narrative review examines the pharmacological, clinical, and safety ambivalence of baclofen across these two indications, comparing efficacy, dosing, and safety profiles, and investigating the “plasticity paradox”: the possibility that baclofen facilitates remyelination in MS while impairing motor learning and cognitive adaptation. Methods: The review draws on clinical trials, meta-analyses, cohort studies, regulatory guidance, and neurobiological research indexed in PubMed/MEDLINE and ScienceDirect (2015–2025), synthesized narratively around the two indications and their clinical overlap. Results: In MS, oral and intrathecal baclofen show a well-defined safety profile, with emerging evidence for neuroprotective effects on remyelination. In AUD, high off-label doses carry risks of toxicity, withdrawal, and cognitive blunting, with efficacy for craving reduction that remains context-dependent and debated. In patients with comorbid MS and AUD, the doses required for anti-craving effects may abolish the compensatory spasticity that preserves motor autonomy, creating competing therapeutic priorities. Conclusions: Baclofen therefore remains versatile but double-edged: indispensable for MS spasticity, yet requiring an individualized, risk-stratified approach in AUD. Selective GABAB allosteric modulators may help resolve this therapeutic tension and represent a promising direction for future neuromodulation research.