Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood despite a growing body of research. Today, our article aims to provide readers with an understanding pertaining to the post-treatment brain changes relative to previously observed acute effects of psilocybin and other ‘psychedelics’ related to clinical outcomes. Additionally, a novel therapeutic mechanism is proposed given new findings.

Introduction

Psilocybin has an ancient and more recent history of medicinal use. Administered in a supportive environment, with preparatory and integrative psychological care, it is used to facilitate emotional breakthrough and renewed perspective. Accumulating evidence suggests that psilocybin with accompanying psychological support can be used safely to treat a range of psychiatric conditions, including: end-of-life anxiety and depression, alcohol and tobacco addiction, obsessive compulsive disorder, and most recently from our group, treatment-resistant major depression. Findings from healthy volunteer studies and trials with other psychedelics supplement those from clinical studies showing that these drugs can have a rapid and lasting positive impact on mental health, often after just one or two doses. Such outcomes raise several important questions, including: what brain mechanisms mediate these effects?

Most human functional neuroimaging studies of psychedelics have focused on their acute effects with the aim of explaining the neural correlates of the psychedelic state. Consistent with findings from animal research, psychedelics appear to dysregulate cortical activity, producing an entropic brain state, characterised by compromised modular but enhanced global connectivity – referred to previously as network disintegration.

• These effects have been found to correlate with important aspects of the psychedelic experience, including ego-dissolution, and were predictive of post-acute changes in the personality domain penness. To our knowledge, only one other very recent study has investigated  12hour post-acute effects of psychedelics on human brain function.

Overview of the Study

The present study focused on changes in brain function before and after psilocybin in patients with treatment-resistant depression who received two doses of the drug (10 mg followed by 25 mg, one-week apart) as part of an open-label clinical trial. Nineteen patients with diagnoses of treatment resistant major depression completed pre-treatment and one-day post-treatment fMRI scanning.

• Arterial spin labelling (ASL) and blood oxygen level dependent (BOLD) resting state functional connectivity (RSFC), were used to measure changes in cerebral blood flow (CBF) and functional connectivity before (baseline) and one-day after treatment with psilocybin (i.e., one day after the 25mg dose).

• It has been suggested that the days after a psychedelic experience constitute a distinct phase, referred to as the after-glow, that is characterised by mood improvements and stress relief. The rationale for scanning one-day post-treatment was to capture brain changes related to this so-called after-glow that might correlate with current mood improvements and/or longer-term prognoses.

The researchers predicted that the resting-state CBF and FC would be altered post treatment and correlate with immediate and longer-term clinical improvements. With regards to longer-term clinical outcomes, they chose to focus on a 5-week post-treatment endpoint due to a virtual 50:50 split between responders and non-responders at this time-point and that none of the patients went on to additional (and thus, confounding) treatments within this time frame. A select number of brain regions of interest were chosen a priori for CBF and RSFC analyses due to previous work implicating their involvement in depression and its treatment.

Summary of Findings

The present study goes some way to addressing an important knowledge gap concerning the post-acute brain effects of serotonergic psychedelics, specifically psilocybin. The findings from the current study 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 disintegration and global integration, 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 interpretation: In this study, they found decreased CBF bilaterally in the temporal lobes, including the left amygdala one-day post treatment. Decreased CBF in subcortical and high-level association cortices have been previously reported with intravenous (I.V.) and now oral psilocybin but increased CBF and metabolism have also been reported with I.V. LSD, oral psilocybin, and oral ayahuasca.

Moreover, much recent research has focused on the involvement of the default-mode network (DMN) in psychiatric disorders, and particularly depression. We previously observed decreased DMN functional integrity under psilocybin and LSD, and others have with ayahuasca. Here however, increased DMN integrity was observed one-day post treatment with psilocybin, both via seed and network-based approaches.

• Previous work has suggested that increased DMN integrity may be a marker of depressed mood and specifically, depressive rumination. On this basis, increased DMN integrity post psilocybin may be surprising. The post-treatment increases in within-DMN resting-state functional connectivity did not relate to symptom improvements. This apparent divergence from previous findings is intriguing and deserves further discussion.

However, in the present study, we saw increased within-DMN resting-state functional connectivity post treatment with psilocybin, which was predictive of treatment response at 5 weeks. These findings suggest a commonality in the antidepressant action of ECT (electro-convulsive therapy) and psilocybin in which DMN integrity is decreased acutely 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 similar results.

In conclusion, the following study established 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 with reductions in depressive mood.

Future Implications

Future research with more rigorous controls should serve to challenge and develop the present study’s findings. 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 in creating novel treatments.