Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

This within-subjects fMRI study (n=19) investigated changes in brain function before versus after psilocybin (with psychological support) in patients with treatment-resistant depression. After treatment, all patients showed decreased depressive symptoms and changes in brain functioning.


“Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.”

Authors: Robin L. Carhart-Harris, Leor Roseman, Mark Bolstridge, Lysia Demetriou, J. Nienke Pannekoek, Matthew B. Wall, Mark Tanner, Mendel Kaelen, John McGonigle, Kevin Murphy, Robert Leech, H. Valerie Curran & David J. Nutt


This paper is included in our ‘Top 10 Articles on Psychedelics in the Treatment of Depression


Psilocybin, a prodrug of psilocin (4-OH-dimethyltryptamine), is a non-selective serotonin 2A receptor (5-HT2AR) agonist and classic ‘psychedelic’ drug that can be used to facilitate emotional breakthrough and renewed perspective. It has been shown to be effective in treating a range of psychiatric conditions.

Most human functional neuroimaging studies of psychedelics focus on their acute effects, with the aim of elucidating the neural correlates of the ‘psychedelic state’. However, few studies have looked at the long-term effects of psychedelic use.

The present study focused on changes in brain function before and after psilocybin treatment in patients with treatment-resistant depression. It was predicted that changes in resting-state CBF and functional connectivity would be altered post treatment and correlate with immediate and longer-term clinical improvements.

We 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 no additional treatments within this time frame.


Nineteen patients with diagnosis of treatment resistant major depression completed pre-treatment and one-day post-treatment fMRI scanning. Psilocybin produced rapid and sustained antidepressant effects, with mean depression scores decreasing from 16.9 5.1 to 8.8 6.2 (change = 8.1 6) and from 18.9 3.1 to 10.9 4.8 (change = 8.4 5.1, t = 6.3, p 0.001). Six of the 15 patients (BOLD) and 16 patients (ASL) met criteria for treatment response at 5 weeks, and all but one patient showed some decrease in depressive symptoms at week 5.

CBF was reduced in the left Heschl’s gyrus, left precentral gyrus, left planum temporale, left superior temporal gyrus, left amygdala, right supramarginal gyrus and right parietal operculum post treatment, but no significant difference was found between responders and non-responders.

Using the BOLD data, seed-based RSFC analyses were performed on the subgenual anterior cingulate cortex, ventromedial prefrontal cortex, bilateral amygdala, and bilateral parahippocampus.

Increased sgACC and vmPFC RSFC were observed post-treatment, but neither correlated with nor predicted treatment response. However, vmPFC-ilPC RSFC increases were significantly greater in responders than non-responders.

A PFC cluster incorporating the lateral and medial prefrontal cortex showed decreased PH RSFC post-treatment, which did not correlate with reductions in depressive symptoms between scan 1 and 2, but did relate to treatment response at 5 weeks. Amygdala RSFC was not significantly altered post treatment.

Reduced RSFC between the DMN and right frontoparietal network and increased RSFC between the sensorimotor network and rFP did not relate to reduced QID-16 scores.

Based on previous work4,5,10, we explored the possibility that the quality of the acute ‘psychedelic’ experience may have mediated the post-acute brain changes. We used scores for the high-dose psilocybin session as a covariate in a correlation analysis.

Patients scoring highest on ‘peak’ or ‘mystical’ experience had the greatest decreases in PH RSFC in limbic and DMN-related cortical regions.


The present study goes some way towards addressing the knowledge gap concerning the post-acute brain effects of serotonergic psychedelics by showing that the 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.

Much recent research has focused on the involvement of the default-mode network in psychiatric disorders, and particularly depression. Here, we observed increased DMN integrity one-day post treatment with psilocybin, both via seed and network-based approaches.

The findings of elevated within-DMN RSFC in depression are not entirely consistent in the literature. For example, lower precuneus-DMN RSFC was seen in patients and normalised after treatment with electroconvulsive therapy (ECT).

psilocybin treatment increased within-DMN RSFC and vmPFC-bilateral ilPC RSFC, which was predictive of treatment response at 5 weeks. This suggests that psilocybin and ECT both affect the DMN, and that this changes the DMN’s integrity.

We found no post-treatment changes in thalamic or sgACC CBF with psilocybin, either in whole-brain or ROI-based Figure 3. Increased coupling between the vmPFC and the displayed regions was predictive of clinical response at 5-weeks posttreatment.

We observed decreased CBF bilaterally in the temporal cortex, including the left medial temporal lobe and specifically, the left amygdala. This could be viewed as a remediation effect, and is consistent with what has previously been reported with ECT45.

Figure 4 shows the relationship between the PH and the displayed regions before and after psilocybin treatment. The decrease in PH coupling was predictive of clinical response at 5-weeks post-treatment.

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 question whether oral psilocybin does indeed cause increases in brain absolute CBF.

The present study found that acute psilocybin-induced changes in parahippocampal RSFC were predictive of treatment response, and that this change was mediated by a decrease in PH-PCC RSFC.

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. These changes were predictive of treatment-response at 5 weeks.

This study is limited by its small sample size and absence of a control condition. Future research should assess the relative contributions of the different treatment factors.


This study was approved by the National Research Ethics Service (NRES) and conducted in accordance with Good Clinical Practice (GCP) guidelines. All patients gave written informed consent.

Figure 5 shows the differences in between-RSN RSFC or RSN ‘segregation’ before and after therapy. Two significant differences did not survive FDR correction for multiple comparisons.

Imaging outcomes were compared to clinical outcomes using the 16-item Quick Inventory of Depressive Symptoms (QIDS-SR16). Relationships between imaging outcomes and contemporaneous decreases in depressive symptoms were calculated using a standard Pearson’s r, and relationships with longer-term changes in depressive symptoms were calculated using a one-tailed t-test.

Anatomical images were acquired using the ADNI-GO recommended MPRAGE parameters on a 3 T Siemens Tim Trio using a 12-channel head coil at Imanova, London, UK.

Functional MRI was acquired with BOLD using T2*-weighted echo-planar images with 3 mm isotropic voxels and 36 axial slices.

Four different imaging software packages were used to analyse the fMRI data. The mean frame-wise displacement (FD) was not significantly different between before and after treatment, and the maximum of scrubbed volumes was 17.3% and 17.7%, respectively. The following pre-processing stages were performed: removal of the first three volumes, de-spiking, slice time correction, motion correction, brain extraction, rigid body registration to anatomical scans, non-linear registration to 2 mm MNI brain, spatial smoothing, band-pass filtering, linear and quadratic de-trending, and regression out 9 nuisance regressors.

We performed seed-based RSFC analyses on the bilateral PH, vmPFC, sgACC and bilateral amygdala based on prior hypotheses. Pre-whitening was applied, and a higher level analysis was performed to compare pre-treatment and post-treatment conditions.

Using Independent Component Analysis (ICA), 12 functionally meaningful Resting State Networks were identified, including the medial visual network, lateral visual network, occipital pole network, auditory network, sensorimotor network, default-mode network, parietal cortex network, and posterior opercular network.

In order to calculate network integrity, 20 HCP ICA components were entered into FSL’s dual regression analysis65. The mean PE across voxels was calculated for each RSN, and paired t-tests were used to calculate the difference in integrity between conditions for each RSN.

Segregation (between-RSN RSFC) was calculated in a similar manner to previous analyses involving acute LSD60 and psilocybin66. A 12 x 12 matrix representing RSFC between different RSN pairs was constructed, and a paired t-test was performed to compare pre-treatment and post-treatment differences on the PE.


This report presents independent research that was supported by the Medical Research Council UK.

Author Contributions

R.L.C.-H. designed the study, acquired the data, wrote the paper, L.R. performed the analyses, M.B. was the principal study psychiatrist, L.D. helped acquire the data, J.N.P. supervised patients and helped construct the scanner ratings, M.B.W.

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, provided you give appropriate credit to the original author(s) and the source.

Study details

Topics studied

Study characteristics
Open-Label Within-Subject Bio/Neuro


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