Psilocybin for treatment-resistant depression : fMRI-measured brain mechanisms, Robin L. Carhart-Harris et al., 2017

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

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

Nature, Scientific Reports, 2017, 7, 13187 |1-11

Doi : 10.1038/s41598-017-13282-7



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.


Psilocybin is the prodrug of psilocin (4-OH-dimethyltryptamine), a non-selective serotonin 2A receptor (5-HT2AR) agonist and classic ‘psychedelic’ drug1. Both compounds occur naturally in the ‘psilocybe’ genus of mushrooms, and are structurally related to the endogenous neurotransmitter serotonin (5-OH tryptamine, 5-HT). 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 perspective2. Accumulating evidence suggests that psilocybin with accompanying psychological support can be used safely to treat a range of psychiatric conditions1, including: end-of-life anxiety and depression3–5, alcohol and tobacco addiction6,7, obsessive compulsive disorder8, and most recently from our group, treatment-resistant major depression9. Findings from healthy volunteer studies10 and trials with other psychedelics11–13 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 a number of 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 elucidating the neural correlates of the ‘psychedelic state’14,15. Consistent with findings from animal research16, psychedelics appear to dysregulate cortical activity14,17, producing an ‘entropic’ brain state18, characterised by compromised modular but enhanced global connectivity – referred to previously as network ‘disintegration’ and ‘desegregation’14. These effects have been found to correlate with important aspects of the ‘psychedelic experience’, including ‘ego-dissolution’14,17,19, and were predictive of post-acute changes in the personality domain ‘openness’20. To our knowledge, only one other very recent study has investigated >12 hour post-acute effects of psychedelics on human brain function (although see12 and now21), and few have looked at anatomical changes possibly related to psychedelic use22,23.

The present study focused on changes in brain function before versus 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. 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 25 mg dose). It has been suggested that the days subsequent to a psychedelic experience constitute a distinct phase, referred to as the ‘after-glow’, that is characterised by mood improvements and stress relief24. 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. We predicted that 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, 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 (QIDS-SR16) and that none of the patients went on to additional (and thus, confounding) treatments within this time frame. A select number of regions of interest were chosen a priori for CBF and RSFC analyses due to previous work implicating their involvement in depression and its treatment, e.g25–27.