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Acamprosate is effective in reducing alcohol intake in weaned alcoholics. We were interested if acamprosate had an effect on the excitability of cortical motoneurons determined by transcranial magnetic stimulation (TMS). We studied 12 male healthy volunteers (mean age 29.5 years, SD = 4.8) who were either treated with 6 tablets of acamprosate (each containing 333 mg verum) per day or placebo (randomized cross-over design) for 1 week. TMS was performed after each treatment session including a paired stimulation paradigm. Motor evoked potentials (MEPs) of the placebo and verum group did not differ with respect to paired stimulation. However, motor threshold increased in the acamprosate group (verum: 61.5% (SD = 7.9) vs. placebo: 58.9% (SD = 8.8), p = 0.036). We conclude that acamprosate leads to a hypoexcitability of the motor cortex. This might be due to subcortical mechanisms, e.g. thalamocortical pathways since intracortical inhibition and facilitation was not affected., (Copyright 2000 S. Karger AG, Basel.)