The present study goes some way to addressing an important knowledge gap concerning the post-acute brain effects of serotonergic psychedelics. Its findings suggest that changes in brain activity observed just one-day after a high dose psychedelic experience are very different to those found during the acute psychedelic state. Specifically, whereas the acute psychedelic state in healthy volunteers is characterised by modular disintegration14,15,28 and global integration14,19,29, there are trends towards modular (re)integration and minimal effects on global integration/segregation post psilocybin for depression. Relating the blood flow findings to what has been seen previously in the acute psychedelic state is somewhat more complicated due to inconsistencies in this literature – likely due to analysis approaches and interpretation14,15,30: Here we saw decreased CBF bilaterally in the temporal lobes, including the left amygdala one-day post treatment. Decreased absolute CBF in subcortical and high-level association cortices have been previously reported with intravenous (I.V.)15 and now oral psilocybin30 but increased CBF and metabolism have also been reported with I.V. LSD14, oral psilocybin31, and oral ayahuasca32.

Much recent research has focused on the involvement of the default-mode network in psychiatric disorders33, and particularly depression34,35. We previously observed decreased DMN functional integrity under psilocybin15 and LSD14, and others have with ayahuasca28. Here however, increased DMN integrity was observed one-day post treatment with psilocybin, both via seed (i.e. vmPFC and sgACC) and network-based approaches. Previous work has suggested that increased DMN integrity may be a marker of depressed mood and specifically, depressive rumination34,36. On this basis, increased DMN integrity post psilocybin may be surprising. The post-treatment increases in within-DMN RSFC and sgACC-PCC RSFC did not relate to symptom improvements but vmPFC-ilPC RSFC did (see Fig. 3). This apparent divergence from previous findings36,37 is intriguing, and deserves further discussion (below).

It should be noted that findings of elevated within-DMN RSFC in depression are not entirely consistent in the literature38,39,40,41. For example, using a DMN-focused analysis, precuneus-DMN RSFC39 was found to be lower in patients than in healthy controls, and normalised after treatment with electroconvulsive therapy (ECT) - and only in responders39 – consistent with the present findings. Lower precuneus-DMN RSFC in depression was also seen in a separate study and the degree of this abnormality correlated with autobiographical memory deficits40. In another study, lower PCC-dmPFC and PCC-ilPC RSFC were seen in first-episode depressed patients relative to healthy controls41. In the present study, we saw increased within-DMN RSFC post treatment with psilocybin, and increased vmPFC-bilateral ilPC RSFC was predictive of treatment response at 5 weeks (Fig. 3). These findings suggest a commonality in the antidepressant action of ECT and psilocybin39 in which DMN integrity is decreased acutely (at least by the latter14,15,28) and increased (or normalised) post-acutely, accompanied by improvements in mood. This process might be likened to a ‘reset’ mechanism in which acute modular disintegration (e.g. in the DMN) enables a subsequent re-integration and resumption of normal functioning.

Recent meta-analyses of studies of resting-state CBF in depression have yielded relatively mixed results34,42, although findings of increased thalamic34,42 and sgACC metabolism are relatively consistent34. Here, we did not find any post-treatment changes in thalamic or sgACC CBF with psilocybin, either in whole-brain or ROI-based analyses. We did observe decreased CBF bilaterally in the temporal cortex however, including the left medial temporal lobe and specifically, the left amygdala. Given previous findings of elevated resting-state amygdala CBF and metabolism in mood disorders25,43,44, the reduction in amygdala CBF observed here, and its relation to symptom severity, could be viewed as a possible remediation effect. Moreover, generalised decreases in CBF are (again) consistent with what has been previously reported with ECT45, i.e. most studies have documented an increase in CBF in the acute ‘ictal’ state, including in the amygdala45; however, the post-ictal period is characterised by decreased CBF, and often in those regions that were most perfused during seizure45. Acutely increased CBF has previously been reported with ayahuasca32 and LSD15 and increased glucose metabolism has been observed in the acute state with oral31 but not I.V. psilocybin15. Thus, a post-acute reversal of acute increases in CBF could be seen as consistent with the post-treatment ‘reset’ mechanism proposed above – although recent work has laid into question whether oral psilocybin does indeed cause increases in brain absolute CBF30. It would be challenging (but not impossible) to carry out acute and post-acute imaging in future trials of psilocybin for depression, and this may be necessary if the ‘reset’ model is to be properly tested. In such a study, we would advise focusing on BOLD RSFC (and perhaps simultaneous EEG-related measures) rather than CBF, due to RSFC and EEG offering more direct and reliable indices of brain activity and function than more difficult to interpret measures such as CBF. The inclusion of a healthy control group, exposed to a consistent treatment procedure, would further strengthen the design of such a study, as would the inclusion of a placebo and/or active comparator arm.

The present study’s other major positive finding was a decrease in RSFC between the bilateral parahippocampus and the PFC, an effect that (like increased vmPFC-ilPC RSFC) was predictive of treatment response at 5 weeks. Curiously, a post-hoc exploratory analysis suggested that acute ‘peak’ or ‘mystical-type’ experiences under psilocybin may mediate the post-acute changes in parahippocampal RSFC (including decreased PH-PCC RSFC). Focusing on parahippocampal-PFC RSFC, this has generally been found to be elevated in depression46, and consistently so across the duration of a resting-state scan47. Prefrontal-limbic circuitry has been linked with top-down suppression of affective responsiveness48 and lower resting-state amygdala-vmPFC RSFC in combination with amygdala hyperfusion was found to relate to state-anxiety in healthy individuals43, corroborating separate findings49. Seven days of citalopram has been found to reduce amygdala-vmPFC50 and dorso-medial PFC-left hippocampal RSFC51 in healthy volunteers, somewhat consistent with the present findings.

In conclusion, here we document for the first time, changes in resting-state brain blood flow and functional connectivity post-treatment with psilocybin for treatment-resistant depression. Decreased blood flow was found to correlate (in the amygdala) with reductions in depressive mood. Increased within-DMN RSFC was observed post-treatment, using both seed and network-based analyses, and specific increases in RSFC between the vmPFC and bilateral ilPC nodes of the DMN were greatest in individuals who maintained treatment-response at 5 weeks. Finally, decreased PH-PFC RSFC was observed post-treatment and this was also predictive of treatment-response at 5 weeks. An exploratory post-hoc analysis revealed that acute ‘peak’ or ‘mystical’ experience during the high-dose psilocybin session was predictive of these changes in PH RSFC.

This study is limited by its small sample size and absence of a control condition. Moreover, correction for multiple testing was applied to the full RSN but not the specific (hypothesis-based) ROI analyses. Future research with more rigorous controls should serve to challenge and develop the present study’s findings and inferences. Assessing the relative contributions of, and potential interactions between, the different treatment factors (e.g. the drug and the accompanying psychological support) may be a particularly informative next step.