Transcranial magnetic stimulation (TMS) and axonal excitability studies have established the presence of cortical and axonal nerve hyperexcitability in ALS, potentially contributing to pathogenesis. MEX is a sodium channel blocker that could reduce hyperexcitability in this disease. 

20 ALS subjects from 10 centers were randomized 1:1:1 to placebo, MEX 300 mg, and MEX 600 mg per day for 4 weeks followed by 4 weeks off treatment. The primary and key secondary endpoints were resting motor threshold (RMT) and motor evoked potential (MEP) amplitude, expressed as percentage of the compound muscle action potential response.

20% of screened subjects were cortically inexcitable. RMT was significantly reduced over 4 weeks with MEX (combined active therapies) compared to placebo by mixed model analysis (mean±SE: placebo=4.7%±2.2, MEX 300 mg=-2.4%±2.3, MEX 600 mg=0.8%±2.2, p=0.039). Dose-dependent reductions of the MEP amplitude was evident at 4 weeks (ratio [95% CI]: placebo=1.308 [0.249 to 0.965], MEX 300 mg=0.589 [0.315 to 1.102], MEX 600 mg=0.490 [0.249 to 0.965], p=0.013). Accommodation half-time was significantly reduced over 4 weeks with MEX (mean±SE: placebo=5.4ms±2.1, MEX 300 mg=-2.6ms±2.1, MEX 600 mg=-1.2ms±2.3, p=0.002).