In this paper, several experimental models of human depression and cognitive dysfunction, which are designed specifically to mimic the proposed mechanisms of action of many nutritional supplements, are illustrated. These mechanisms of interest are antioxidant effects, glucose utilization, neuronal membrane function and neurotransmitter effects, with particular reference to nutrient-based amino acid manipulations of neurotransmission, such as tryptophan depletion. It is concluded that the application of experimental human models of altered mood and cognitive function may illuminate substantially the quest for nutritional enhancement of human mood and cognitive function.