The objective of this trial was to determine the safety and tolerability of memantine in patients with sporadic ALS and to examine changes in CSF biomarkers during drug therapy. Twenty patients on stable doses of riluzole were enrolled. Patients received memantine, 10 mg b.i.d., for 18 months. Lumbar punctures were performed at baseline, six and twelve months. The ALSFRS was measured at six weeks, 3, 6, 9, 12 and 18 months. Results showed that patients treated with memantine and riluzole had an average rate of decline on the ALSFRS of -0.73 points per month. Patients who progressed faster than -0.5 ALSFRS points per month had an average baseline CSF tau concentration of 574 pg/ml, while those who progressed slower than -0.5 ALSFRS points per month had CSF tau levels that averaged 298 pg/ml (p = 0.006). After therapy with memantine, patients had a 27% decline in CSF tau levels (p = 0.04) and four patients whose CSF tau dropped to healthy control levels lost only -0.42 ALSFRS points per month. In conclusion, memantine was well tolerated in patients with ALS. Patients receiving memantine and riluzole lost on average -0.73 ALSFRS points per month. Furthermore, levels of CSF tau at baseline could be correlated with how rapidly a patient's disease progressed.