The effectiveness and safety of memantine for headache are elusive, and this meta-analysis aimed to explore the influence of memantine versus placebo for headache.

We searched PubMed, Embase, Web of science, EBSCO, and Cochrane library databases through May 2021 and included randomized controlled trials reporting memantine versus placebo for headache patients. This meta-analysis was performed using the random-effects model.

Our meta-analysis included 4 randomized controlled trials and 229 patients. Compared with control group for headache, memantine treatment could substantially reduce headache days (mean difference [MD] = −3.10; 95% confidence interval [CI] = −5.46 to −0.75; P = 0.01), pain intensity (MD, −0.43; 95% CI, −0.85 to −0.01; P = 0.04), monthly attack frequency (MD, −2.14; 95% CI, −2.83 to −1.46; P < 0.00001), and Migraine Disability Assessment Test (MD, −5.63; 95% CI, −6.46 to −4.79; P < 0.00001) but revealed no significant influence on days for acute pain medications, adverse events, or nausea/vomiting.

Memantine treatment is effective and safe to treat headache.