Psychedelic substances such as psilocybin and ketamine may represent the future of antidepressant treatment, due to their rapid and prolonged effects on mood and cognition. The current body of psychedelic research has focused on administration and treatment within a psychiatric context. Here, instead, we put to the test the contention that it is necessary to evaluate the current state of this literature from a broader biopsychosocial perspective. Examining these arguably neglected social and psychological aspects of psychedelic treatment can provide a more holistic understanding of the interplay between the interconnected domains. This review of six major clinical trials applies a biopsychosocial model to evaluate the antidepressant effects of psilocybin and ketamine assisted therapy. We conclude that combination psychedelic treatment and psychotherapy facilitate more enduring and profound antidepressant effects than produced by ketamine or psilocybin alone. Emphasising the advantages of therapeutic intervention will encourage those who may attempt to self-medicate with psychedelics to instead seek a framework of psychological support, minimising associated risks of unregulated use.