AimThis article proposes a literature review focused on the so-called “classic” psychedelics (LSD, psilocybin, DMT, and mescaline) and, more specifically, on their use in the psychotherapy of major depressive disorders and the way they affect symbolization processes. MethodAfter some introductory remarks on psychedelics and depressive disorders, we describe some modern clinical trials, and then explore the peculiar phenomenology occurring in the psychedelic experience, as well as its therapeutic effects on depressive symptoms. The underlying mechanisms are discussed from a perspective at the crossroads of cognitive neurosciences and psychoanalysis. We conclude with some reflections on the crucial role of the setting. ResultsThe results already obtained suggest that a single dose, taken in a supportive environment, may be sufficient to produce significant and immediate therapeutic effects, which are still present six months after the dose, although less so for some patients. Clinical response depends on the subjective aspects of the individual experience. More specifically, it seems correlated with the ability to “let go” and to allow autobiographical memories to emerge, along with the intense emotions they carry. It also relies on the presence and intensity of mystical-type experiences, characterized by feelings of “ego dissolution,” unity with everything, transcendence of space and time, and ineffability. DiscussionPsychedelic-assisted therapy seems to promote the emergence of primary processes and the lifting of defense mechanisms. Psychedelics would thus catalyze the resumption of symbolization processes, favoring in particular the integration of unconscious conflicts as well as the remodeling of pathogenic object relationships. On the neurobiological level, these processes would be underpinned by a decrease in the activity of the default mode network – sometimes considered the primary biologic substrate of the Freudian ego –, associated with an increase in brain entropy and in neuroplasticity. These different elements entail a decrease in depressive symptomatology, particularly ruminations. Common factors identified as the cause of positive changes in classical psychotherapies appear naturally amplified in the psychedelic experience, which requires the containing function of a therapist and a supportive clinical setting to allow a resumption of symbolic processes. To ensure the perpetuation of the observed transformations, which often exceed the simple withdrawal of symptoms, an extended psychotherapeutic monitoring would be appropriate. ConclusionThe psychedelic substance acts as a catalyst, allowing an access to otherwise inaccessible unconscious materials, which can then be processed both spontaneously and within the therapeutic relationship. Considering the data discussed in this review, we emphasize the need for further research exploring the potential of this treatment, which also offers the hope of a renewed dialogue between psychiatry and psychology, neurosciences and psychoanalysis.