The application of operant conditioning with EEG variables to produce changes in behavior has been gaining increasing interest in research and application areas. However, the methodology has come under scrutiny and criticism for its potential placebo effects. This article will examine those issues from the traditional methodologies of demonstrating effectiveness (control group, sham treatments) as well as examine the possible biochemical and electrophysiological effects of a placebo response. Specifically, the role of endorphins and dopamine and their relationship to the alpha and beta frequency in the placebo response will be examined. The research addressing the diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) correlates of the intervention will be examined.