5-HT2 receptors regulate sleep including yawning behavior. Ritanserin, a selective 5-HT2A receptor antagonist, increases the duration of slow wave in rats and humans. This effect is more pronounced during the light period when melatonin plasma levels are low; melatonin inhibits the sleep effects of ritanserin. These findings indicate that melatonin co-determines the effects of ritanserin on sleep. In a cohort of multiple sclerosis (MS) patients ketanserin, a selective 5-HT2A receptor antagonist, induces recurrent yawning particularly when administered in daytime. The frequency of yawning induced by the drug was modified by AC pulsed picotesla flux electromagnetic fields (EMFs) which affect melatonin secretion. Two MS patients are presented in whom the frequency of ketanserin-induced yawning was altered in opposite directions by these EMFs. The first patient, a 50 year old woman with a remitting-relapsing course, developed recurrent yawning and sleepiness after administration of ketanserin (10 mg, PO). Yawning was decreased dramatically during application of EMFs but was unaffected by a placebo EMFs treatment. The second patient, a 35 year old man with a chronic progressive course, manifested a single and brief yawn after administration of an equal dose of ketanserin. Yawning was increased dramatically during application of EMFs while remaining unchanged during a placebo EMFs treatment. These observations demonstrate a bidirectional effect of picotesla flux EMFs on ketanserin-induced yawning which may be related to differences in daytime melatonin plasma levels among MS patients. If validated by estimations of melatonin plasma levels in a larger cohort of patients the information derived from the effects of picotesla EMFs on ketanserin-induced yawning could be used to: (a) assess pineal melatonin functions in patients with MS; (b) indicate differences in pineal functions between male and female MS patients; and (c) indicate a relationship between plasma melatonin levels and the fatigue of MS.