Neural Correlates of Psilocybin-Assisted Psychotherapy in Depressive Disorders : A Systematic Review of fMRI Studies

Depression is a mental disorder that severely affects one's ability to function in life. Though traditional psychological, pharmacological, and somatic treatments are available - patients often experience adverse side effects and do not achieve remission, pointing towards a treatment gap. Recently, psychedelic-assisted psychotherapy (PAP) has gained renewed interest as a potential treatment for depression. This systematic review aims to create a better understanding of the neural mechanisms involved, as investigated with functional Magnetic Resonance Imaging (fMRI), in psilocybin-assisted psychotherapy in the treatment of depression. A literature search was conducted in the following databases: Web of Science, Medline EBSCO and Scopus, with keywords such as “psilocybin or psilocin” and “depression or major depressive disorder or MDD” and “fMRI”, from 2015-01-01 to 2024-12-31. The search yielded a total of 126 results, of which seven articles met the final inclusion criteria. Results showed that a decrease in depressive symptoms after psilocybin-assisted psychotherapy correlated with decreased brain-network modulation, increased functional connectivity (FC) in several brain networks, and region-specific hierarchical reconfigurations (particularly in posterior cingulate cortex, rostral anterior cingulate cortex, amygdala and hippocampus). In conclusion, psilocybin-assisted psychotherapy shows great promise as a contender for traditional depression treatments by targeting the underlying neural mechanisms involved in depression. Its mind-altering effects foster new perspectives that may alleviate the emotional blunting and negativity bias often seen in depression. Further research with larger samples and longitudinal designs is necessary to confirm and expand upon these findings.