Expectancy has been proposed as an important mechanism that contributes substantially to beneficial therapeutic outcomes in a variety of clinical settings. Expectancy and classical conditioning paradigms each rely upon past experience, learning and memory. For this reason, it has been suggested that expectancy and classical conditioning may share common mechanistic pathways. Thus, conditioned responses in animal models may provide useful experimental systems in which to advance our understanding of the underlying mechanisms linking expectancy to beneficial outcomes. In preliminary results presented with this proposal, we show that it was possible to induce a conditioned, beneficial therapeutic response in mice with the CNS autoimmune disease, experimental autoimmune encephalomyelitis (EAE). The acquisition of the conditioned response was achieved by the paired administration of saccharin flavored drinking water (the conditioned stimulus, CS) and an effective experimental treatment agent, alpha lipoic acid (ALA) administered subcutaneously (the unconditioned stimulus, UCS). Expression of the conditioned therapeutic response was detected as reduced disease severity resulting from administration of the conditioned stimulus, saccharin. The mechanisms responsible for integrating saccharin administration with clinical amprovement in EAE are not understood. Such mechanisms represent potentially powerful complementary pathways capable of enhancing expectancy and beneficial clinical outcomes. In order to understand these processes, this pilot proposal seeks to develop the conditioned therapeutic response in EAE as a potentially useful model of complementary and alternative therapy.