Ketamine solutions did not form a film (pi=0) but had an appreciable surface potential (delta V=500 mv), indicating a significant array of +/- oriented charge dipoles at the air-water interface, as opposed to calcium chloride solutions whose delta V was zero. The delta V values of ganglioside films spread on the aqueous phase varied in the order water less than sodium chloride less than calcium chloride less than ketamine hydrochloride. At equivalent concentrations, calcium chloride was 500 times as effective as sodium chloride, and ketamine at the clinical concentrations of 10-20 microgram/ml (36-72 micrometer) was 6000 times as effective as calcium chloride in raising the surface potential of gangliosides; the delta V effect with mitochondrial lipid was in the reverse order; water less than sodium chloride = ketamine hydrochloride less than calcium chloride. This calcium-ketamine inversion indicates a unique specificity of ketamine for gangliosides. Since ketamine acts on the brain and did not affect mitochondrial respiration, the surface potential data suggest that part of the mechanism of action of ketamine could be its interaction with synaptic surfaces and, specifically, with the sialic acid of gangliosides and/or glycoproteins present on the synaptic membrane surface.