Despite the popular support for psychedelics as aids for depression, academics and the public frequently overestimate the efficacy of available medications and psychotherapies. Metaanalyses reveal that antidepressant medications alone help only one in four patients and rarely surpass credible placebos. Their effects, though statistically significant, might not impress depressed patients themselves. Psychotherapies create better outcomes than antidepressant drugs alone; combining the two provides measurable advantages. Nevertheless, the best combinations help only 65% of the clients who complete treatment. The drugs create side-effects and withdrawal surprisingly more severe than professional guidelines imply, too. Psychedelics appear to improve depression through some of the same mechanisms as psychotherapy, as well as some novel ones, suggesting that the combination could work very well. In addition, subjective experiences during the psychedelic sessions covary with improvement. Guiding clients to focus on these targeted thoughts and feelings could improve outcome. These data underscore the serious need for clinical trials of psychedelic-assisted, empirically supported treatment for depression with guided experiences during the psychedelic session. These trials would require important components to maximize their impact, including meaningful preparatory sessions designed to enhance motivation and explain empirically supported approaches, guided administration sessions that focus on oceanic boundlessness, integration sessions that support progress, and follow-up sessions consistent with established research. This combination involves markedly more than a simple pairing of medication and talk therapy, but proper application could have an unparalleled impact on public health.