Efficacy and Tolerability of Zonisamide for Alcohol Use Disorder

PURPOSE: Zonisamide, an anticonvulsant with GABAergic and glutamatergic effects, has been investigated as a treatment for alcohol use disorder (AUD), but its efficacy and tolerability remain uncertain. This systematic review and meta-analysis synthesizes evidence from randomized controlled trials evaluating zonisamide for AUD. PROCEDURES: We searched MEDLINE, Embase, PsycINFO, Scopus, and CENTRAL from inception through June 23, 2025, with an updated search on March 31, 2026, for randomized controlled trials comparing zonisamide to placebo in adults with AUD. The primary outcome was a reduction in alcohol use. Data were pooled using random-effects meta-analyses. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. FINDINGS: Five randomized controlled trials (N=344) met inclusion criteria. Zonisamide significantly reduced drinks per day (MD=-0.79; 95% CI=-0.95 to -0.63; P<0.001) and drinking days (MD=-7.93; 95% CI=-11.03 to -4.83; P<0.001). No significant effect was observed for heavy drinking days (MD=-0.95; 95% CI=-2.12 to 0.22; P=0.11), with high heterogeneity (I²=91%). Zonisamide was associated with a significantly lower rate of nervousness, anxiety, or irritability (RR=0.53; 95% CI=0.34-0.84; P=0.007); other adverse events did not differ from placebo. IMPLICATIONS: Zonisamide reduced drinks per day and drinking days but not heavy drinking days, suggesting a selective benefit on overall consumption. A protective effect on nervousness, anxiety, and irritability was also observed, consistent with zonisamide's GABAergic mechanism. Further well-powered trials are needed to inform clinical recommendations.