Despite reports of apparent benefits, social and political pressure beginning in the late 1960s effectively banned scientific inquiry into psychedelic substances. Covert examination of psychedelics persisted through the 1990s; the turn of the century and especially the past 10 years, however, has seen a resurgent interest in psychedelic substances (eg, LSD, ayahuasca, psilocybin). This chapter outlines relevant EEG and brain imaging studies evaluating the effects of psychedelics on the brain. This chapter also reviews evidence of the use of psychedelics as adjunct therapy for a number of psychiatric and addictive disorders. In particular, psychedelics appear to have efficacy in treating depression and alcohol-use disorders.