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

In this open-label study (n=24) depressed patients were given psilocybin (25mg/70kg) and the effects of psilocybin therapy on cognitive flexibility, neural flexibility and neurometabolite concentrations were assessed. While it was found that depressive symptoms were reduced, interestingly, it was also found that increased dynamics of functional connectivity (dFC) between the anterior and posterior cingulate cortices (ACC/PCC) predicted improvements in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility.


“Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.”

Authors: Manoj K. Doss, Michal Považan, Monica D. Rosenberg, Nathan D. Sepeda, Alan K. Davis, Patrick H. Finan, Gwen S. Smith, James J. Pekar, Roland R. Griffiths & Frederick S. Barrett


How psychedelics exert their effects on the brain remains somewhat of a mystery. Understanding these neurophysiological mechanisms is essential in order to advance the medicalization of psychedelics. Thanks to modern neuroimaging techniques, researchers are constantly discovering more and more about these potential mechanisms.

In the present study, researchers at Johns Hopkins assessed the effects of psilocybin-assisted therapy on a number of neurological variables in patients who are depressed. These variables include; cognitive flexibility (the ability to adapt our behaviour and thinking in response to the environment), neural flexibility and neurometabolite concentrations. As well as using fMRI to assess these variables, the researchers created predictive models using the data in order to gain a deeper understanding of the neurophysiological effects elicited by psilocybin.

Main findings

  • Psilocybin therapy was shown to increase cognitive and neural flexibility in patients with major depressive disorder.
  • There was a lack of correlation between improvements in cognitive flexibility and improvements in depression, suggesting that cognitive flexibility may not be mechanistically related to the antidepressant effects of psilocybin therapy.
  • One week after treatment glutamate and N-acetylaspartate levels were decreased in the anterior cingulate cortex (ACC) suggesting that a decrease in neural metabolism may increase neural flexibility although further research is needed to establish this link.
  • Larger pre- to post-treatment increases in dynamics of functional activity (dFC) between the ACC and the posterior cingulate cortex (PCC) and greater baseline dFC of the ACC was associated with fewer improvements in cognitive flexibility.

Overall, these findings suggest a new relationship between cognitive and neural flexibility. Practical implications of such findings suggest that patients with lower baseline neural flexibility may be more likely to benefit from psychedelic therapy. Such findings provide us with further insight with regards to how psychedelics may exert their effects and help us to further develop treatment models using psychedelics.

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