Baclofen is a GABA-B receptor agonist primarily used for spasticity. It is increasingly prescribed orally at high, off-label doses for conditions such as alcohol use disorder, raising concerns regarding severe toxicity and withdrawal syndromes. This systematic review comprehensively characterizes the clinical presentations, management strategies, and outcomes associated with oral baclofen toxicity and withdrawal.

MEDLINE, Embase, and CENTRAL databases were searched from inception through October 2024. Eligible studies included clinical trials, observational studies, case series and case reports. Three reviewers independently performed data extraction and quality assessments using the Joanna Briggs Institute (JBI) critical appraisal checklists for case reports and case series. Findings were synthesized narratively.

Sixty-six case reports (44 toxicity cases from 38 case reports, 34 withdrawal cases from 28 case reports) and 18 retrospective studies (n = 1,540) were included. Baclofen toxicity commonly presented with CNS depression, coma, seizures, and cardiovascular instability, particularly at doses ≥300 mg. Management predominantly involved supportive measures, including mechanical ventilation. Full clinical recovery occurred in 97.7% of cases; overall mortality was 2.3%. Baclofen withdrawal commonly manifested with severe psychiatric disturbances, delirium, agitation, and autonomic instability. Rapid baclofen reinitiation consistently resolved withdrawal symptoms.