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

Classic psychedelics, such as psilocybin, have shown promise in treating psychiatric disorders, including MDD. Unlike SSRIs, psilocybin demonstrates rapid and enduring antidepressant effects, potentially through neuropsychoplastogenic mechanisms. Cognitive flexibility, the ability to adapt cognitive operations to changing demands, is often impaired in MDD and other disorders treatable with psychedelics. Deficits in cognitive flexibility might precede other depressive symptoms, potentially representing an endophenotype. Improving cognitive flexibility could be particularly beneficial in the context of psychotherapy. While some antidepressants improve cognitive flexibility, many patients remain treatment-resistant. The acute effects of 5-HT2A receptor modulation on cognitive flexibility are mixed, with both impairment and enhancement reported in animal and human studies. The anterior cingulate cortex (ACC) and its interactions with other brain regions, particularly the posterior cingulate cortex (PCC), are crucial for cognitive flexibility. Psychedelics modulate ACC activity and functional connectivity, but the long-term effects on cognitive and neural flexibility in MDD patients remain unclear. This study aimed to investigate the enduring effects of psilocybin therapy on cognitive and neural flexibility in MDD patients using multimodal brain imaging and cognitive tasks.

Existing research suggests a potential link between classic psychedelics and improved cognitive flexibility, though the acute effects of 5-HT2A receptor modulation (the primary receptor targeted by psychedelics like psilocybin) on cognitive flexibility are inconsistent across studies. Some studies show impairment, while others show enhancement, depending on animal model and methodology. The role of 5-HT2C receptor co-activation is also complex. The ACC is critical for cognitive flexibility, and psychedelics acutely alter ACC activity and connectivity. However, the long-term impact of psychedelics on ACC function and its relationship to cognitive flexibility in MDD patients requires further investigation. Studies have indicated that psychedelics induce neural plasticity, potentially through changes in functional connectivity measured with fMRI. Previous studies of the lasting impact of psychedelics on neural flexibility yielded mixed results, with one small study finding no enduring effects. This study aims to address the gap in knowledge regarding the enduring effects of psilocybin therapy on both cognitive and neural flexibility in patients with MDD.

This open-label clinical trial (NCT01318930) included 24 participants (8 males) aged 24-59 with MDD. Participants were recruited through advertisements and referrals. Exclusion criteria included current antidepressant medication, recent psychedelic use, significant medical conditions, and family history of psychotic disorders. Participants were randomly assigned to immediate or delayed treatment groups. The immediate group underwent baseline assessments, preparatory therapy, two psilocybin sessions (200 mg/70kg and 30 mg/70kg), and follow-up meetings. The delayed group completed assessments and were monitored for 8 weeks before receiving the same treatment. Depression was assessed using the GRID-HAMD. Cognitive flexibility was measured using the Penn Conditional Exclusion Test (PCET), a set-shifting task. Neuroimaging (7T fMRI and MRS) was conducted approximately 4 weeks before and 1 week after the second psilocybin session. fMRI data included T1-weighted structural MPRAGE and task-free (eyes open) BOLD fMRI. MRS scans focused on the ACC, left and right hippocampi. Data preprocessing included motion correction, co-registration, normalization, and noise reduction. Analyses involved ANOVAs, t-tests, Pearson correlations, and connectome-based predictive modeling to examine the relationship between baseline functional connectivity (sFC and dFC) and changes in depression and cognitive flexibility. The focus was on ACC-PCC connectivity due to their roles in cognitive flexibility and psychedelic action.

Psilocybin therapy significantly reduced GRID-HAMD scores (indicating improved depression), and this reduction was sustained at 1 and 4 weeks post-treatment. Cognitive flexibility, as measured by perseverative errors on the PCET, also significantly improved from baseline to 1 and 4 weeks post-treatment. Importantly, changes in depression scores were not correlated with changes in cognitive flexibility scores. One week post-psilocybin therapy, glutamate and NAA concentrations decreased significantly in the ACC but not in the hippocampi. Increased dFC between the ACC and PCC was observed one week post-treatment. However, a surprising negative correlation was found between the increase in ACC-PCC dFC and improvement in cognitive flexibility, suggesting that greater increases in dFC may be associated with less improvement in cognitive flexibility. Connectome-based predictive modeling revealed that baseline sFC and dFC from the ACC predicted changes in cognitive flexibility post-treatment. Higher baseline dFC was associated with better baseline cognitive flexibility but less improvement post-treatment.

This study demonstrates that psilocybin therapy produces enduring improvements in cognitive flexibility in patients with MDD, independent of its antidepressant effects. The lack of correlation between improvements in cognitive flexibility and depression suggests distinct mechanisms underlying these effects. The decreased glutamate and NAA concentrations in the ACC after psilocybin administration may reflect neuroplastic changes. The unexpected negative correlation between increased ACC-PCC dFC and improvement in cognitive flexibility requires further exploration. It suggests a nuanced relationship between neural and cognitive flexibility, possibly indicating that patients with lower baseline neural flexibility may benefit more from psilocybin therapy. The findings contribute to a growing body of evidence suggesting that psychedelics can modulate neural circuits involved in cognitive flexibility, offering potential new avenues for treating cognitive dysfunction in MDD.

This study provides compelling evidence for the enduring positive effects of psilocybin therapy on cognitive flexibility in MDD patients. The findings highlight a complex interplay between neural and cognitive flexibility, suggesting that baseline neural flexibility may predict treatment response. Future research should investigate the underlying mechanisms involved and explore personalized treatment approaches based on baseline neural characteristics. Larger, placebo-controlled trials are needed to confirm these findings and further elucidate the mechanisms of action.

This study's open-label design precludes definitive conclusions about causality. The absence of a placebo control group leaves open the possibility of placebo effects contributing to the observed improvements. The relatively small sample size limits the generalizability of the findings. Future studies should utilize larger sample sizes and employ placebo-controlled designs to strengthen the causal inferences and improve generalizability. The focus on specific brain regions may overlook potentially important contributions from other areas involved in cognitive flexibility.