The “Magic Capsule”: The Therapeutic Potential of Psilocybin in the Treatment of Major Depressive Disorder (MDD)

Abstract

Depression is one of the leading global public health challenges, producing socioeconomic consequences and significantly affecting individuals’ quality of life. The clinical situation is particularly concerning in cases of Major Depressive Disorder (MDD) classified as Treatment-Resistant Depression (TRD), in which patients do not achieve a satisfactory response to conventional pharmacological treatments. Given the limitations of the model based on the monoamine hypothesis and the use of Selective Serotonin Reuptake Inhibitors (SSRIs), the so-called “Psychedelic Renaissance” has emerged, marked by renewed clinical research on substances such as psilocybin, an alkaloid found in mushrooms of the genus Psilocybe. Through a qualitative and exploratory integrative literature review, this study analyzes the neurobiological mechanisms of psilocybin, particularly its effects on the temporary disruption of the Default Mode Network and the induction of structural and functional neuroplasticity. However, it challenges the reductionist notion of the “magic capsule,” according to which psychedelics act independently as super-antidepressants. In contrast, the Assisted Synaptic Adaptation Theory is presented, understanding psilocybin as a biological catalyst capable of opening a temporary window of neural flexibility. It is concluded that therapeutic effectiveness depends on combining the substance with structured psychotherapeutic support throughout the preparation, supervision, and integration stages. This association may guide synaptic reorganization, facilitate the reframing of experiences, and promote sustained remission of depressive symptoms in patients with treatment-resistant depression.