To investigate different cortical effects of lamotrigine and valproic acid, 30 paid healthy adult men were given, in a randomized/blinded fashion on three separate days (separated by a week), either a single dose of lamotrigine 325 mg, or a single dose of valproic acid 1,250 mg, or placebo. Resting motor threshold (RMT), cortical silent period (CSP) and motor evoked potential recruitment curves (RC) were assessed at baseline and 3 h after administration of each medication (or placebo). Lamotrigine caused a significant increase (63.32 vs. 69.25) in the RMT, compared with an insignificant increase following valproic acid (62.50 vs. 63.35), and a decrease (62.60 vs. 62.36) following placebo (F (2,26) = 18.58, P < 0.0001). No significant difference in CSP was found between placebo and drugs (F (2,26) = 0.119, P > 0.05). RCs were significantly suppressed by lamotrigine (t = 2.07, P < 0.05) and enhanced by valproic acid (t = 2.39, P < 0.05). Lamotrigine and valproic acid have different effects on cortical neuronal excitability as demonstrated by TMS.