Trial PaperDepressive DisordersNeuroimaging & Brain MeasuresTreatment-Resistant Depression (TRD)Psilocybin

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

Psilocybin with psychological support produced rapid symptom reductions in treatment‑resistant depression and, on fMRI, elicited post‑treatment decreases in temporal cortex cerebral blood flow including the amygdala (the latter correlating with symptom improvement) alongside increased resting‑state functional connectivity within the default‑mode network. Increased vmPFC–bilateral inferior lateral parietal connectivity and decreased parahippocampal–prefrontal connectivity predicted 5‑week response, prompting the authors to propose a post‑acute “reset” therapeutic mechanism distinct from acute psychedelic effects.

Authors

  • Robin Carhart-Harris
  • David Nutt
  • Leor Roseman

Published

Scientific Reports
individual Study

Abstract

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.

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Research Summary of 'Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms'

Introduction

Psilocybin, a serotonin 2A receptor agonist and the active prodrug psilocin, is showing clinical promise when administered with preparatory and integrative psychological support, but the neural mechanisms that underlie its antidepressant effects remain poorly understood. Earlier human imaging work has mainly characterised the acute psychedelic state, reporting a more entropic brain configuration with modular disintegration and enhanced global connectivity that correlates with aspects of the subjective experience such as ego-dissolution. Few studies, however, have examined brain function beyond the acute phase (>12 hours) in clinical populations, leaving a gap about post-acute or 'after-glow' changes that might relate to mood improvement and longer-term outcomes. Carhart-Harris and colleagues set out to characterise cerebral blood flow (CBF) and resting-state functional connectivity (RSFC) changes before versus one day after psilocybin treatment in patients with treatment-resistant depression (TRD). Patients received two oral doses (10 mg then 25 mg one week apart) within an open-label clinical protocol. The investigators tested whether post-treatment CBF and BOLD RSFC would be altered relative to baseline and whether such changes would correlate with immediate mood improvements and with clinical response at a 5-week endpoint. A priori regions of interest (ROIs) implicated in depression and its treatment were selected for focussed analyses, and broader network-level assessments of 12 canonical resting-state networks were also performed.

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Study Details

Related Clinical Trial

Completed

Imperial College London Open-Label Psilocybin Pilot for Treatment-Resistant Depression (Carhart-Harris / Lyons 2016–2018)

Open-label, uncontrolled pilot study of oral psilocybin for treatment-resistant depression at Imperial College London (Front Psychol 2018; Lyons T, Carhart-Harris RL; PMID 30369890; DOI 10.3389/fpsyg.2018.01721; also reported: Carhart-Harris et al. Lancet Psychiatry 2016 n=12, Neuropharmacology 2018 n=20). n=15 TRD patients + 15 healthy controls matched on age/gender/education. Patients: clinically assessed TRD. Intervention: oral psilocybin 10 mg (safety dose) one week before oral psilocybin 25 mg (treatment dose); unblinded, open-label. Outcomes in this paper: future-event forecasting (optimism bias test) at baseline and 1 week post-25 mg session; QIDS-SR depression at baseline and 1 week. Neither patients nor research team masked to treatment. UK regulatory/ethics approval obtained. No CT.gov registration found (searches by PMID, Carhart-Harris, and TRD+psilocybin+UK). Possible ISRCTN or NHS HRA registration not confirmed from available metadata.

Started
Type
interventional
Randomized
No
Registry ID
CARHART-HARRIS-2016-LANCETPSYCH-PSILOCYBIN-TRD-IMPERIAL

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211 cited
Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function

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5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety

Davis, A. K., So, S., Lancelotta, R. et al. · The American Journal of Drug and Alcohol Abuse (2019)

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Microdosing psychedelics: personality, mental health, and creativity differences in microdosers

Anderson, T., Petranker, R., Rosenbaum, D. et al. · Psychopharmacology (2019)

142 cited
Psychiatry might need some psychedelic therapy

Johnson, M. W. · International Review of Psychiatry (2018)

Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions

Richards, W. A., Garcia-Romeu, A. · International Review of Psychiatry (2018)

Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression

Roseman, L., Demetriou, L., Wall, M. B. et al. · Neuropharmacology (2018)

More realistic forecasting of future life events after psilocybin for treatment-resistant depression

Lyons, T., Carhart-Harris, R. L. · Frontiers in Psychology (2018)

49 cited
Psychedelics and music: neuroscience and therapeutic implications

Barrett, F. S., Preller, K. H., Kaelen, M. · International Review of Psychiatry (2018)

Psychedelics as anti-inflammatory agents

Flanagan, T. W., Nichols, C. D. · International Review of Psychiatry (2018)

Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development

Schenberg, E. E. · Frontiers in Pharmacology (2018)

Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination

Grimm, O., Kraehenmann, R., Preller, K. H. et al. · European Neuropsychopharmacology (2018)

Taking Psychedelics Seriously

Byock, I. · Journal of Palliative Medicine (2018)

The entropic brain - revisited

Carhart-Harris, R. L. · Neuropharmacology (2018)

Increased nature relatedness and decreased authoritarian political views after psilocybin for treatment-resistant depression

Lyons, T., Carhart-Harris, R. L. · Journal of Psychopharmacology (2018)

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

Carhart-Harris, R. L., Bolstridge, &. M., Day, C. M. J. et al. · Psychopharmacology (2017)

Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression

Stroud, J., Freeman, T. P., Leech, R. et al. · Psychopharmacology (2017)

88 cited
Serotonin and brain function: a tale of two receptors

Carhart-Harris, R. L., Nutt, D. J. · Journal of Psychopharmacology (2017)

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