Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial

Muscle Nerve. 2021 Mar;63(3):371-383. doi: 10.1002/mus.27146. Epub 2020 Dec 31.


Background: To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial.

Methods: Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).

Results: RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.

Conclusions: The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.

Keywords: amyotrophic lateral sclerosis; axonal excitability; outcome research; randomized controlled clinical trial; transcranial magnetic stimulation.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Axons*
  • Cortical Excitability*
  • Double-Blind Method
  • Electrodiagnosis
  • Electromyography
  • Evoked Potentials, Motor / physiology
  • Female
  • Humans
  • Male
  • Median Nerve / physiopathology
  • Mexiletine / therapeutic use*
  • Middle Aged
  • Neural Conduction / physiology
  • Preliminary Data
  • Transcranial Magnetic Stimulation
  • Voltage-Gated Sodium Channel Blockers / therapeutic use*


  • Voltage-Gated Sodium Channel Blockers
  • Mexiletine