Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder

This open-label study investigated the enduring effects of psilocybin therapy on cognitive and neural flexibility in 24 patients with major depressive disorder (MDD). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, but this improvement wasn't correlated with antidepressant effects. One week post-therapy, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and dorsal functional connectivity (dFC) increased between the ACC and posterior cingulate cortex (PCC). Surprisingly, greater ACC-PCC dFC increases were linked to less cognitive flexibility improvement. Connectome-based predictive modeling showed baseline dFC from the ACC predicted cognitive flexibility improvements, with higher baseline dFC associated with better baseline flexibility but less post-treatment improvement, suggesting a complex relationship between cognitive and neural flexibility.

Manoj K. Doss, Michal Povážan, Monica D. Rosenberg, Nathan D. Sepeda, Alan K. Davis, Patrick H. Finan, Gwenn S. Smith, James J. Pekar, Peter B. Barker, Roland R. Griffiths, Frederick S. Barrett