Decreased brain modularity after psilocybin therapy for depression

This preprint (2021) analyzed data from an open-label (n=16) and a randomized double-blind placebo-controlled study (n=43) of psilocybin (10 – 25mg) treatment for depression, in order to identify neural biomarkers underlying antidepressant efficacy. Psilocybin (but not escitalopram) decreased brain modularity across both trials, i.e. brain connectivity became less segregated, and this correlated with improvements in depressive symptomatology.


Objective To assess the sub-acute impact of psilocybin on brain activity in patients with depression. 

Design Pre vs post-treatment resting-state functional MRI (fMRI) was recorded in two trials: 1) Open-label treatment-resistant depression (TRD) trial with baseline vs 1 day post-treatment fMRI (April-2015 to April-2016); 2) Two-arm double-blind RCT in major depressive disorder (MDD), fMRI baseline vs 3 week after psilocybin-therapy or 6 weeks of daily escitalopram (January-2019 to March-2020).  

Setting Study visits occurred at the NIHR Imperial Clinical Research Facility.

Participants Adult male and female patients with TRD or MDD.  

Intervention(s) (for clinical trials) or Exposure(s) (for observational studies) Study 1: Two oral doses of psilocybin (10mg and 25mg, fixed order, 7 days apart). fMRI was recorded at baseline and one day after the 25mg dose. Study 2: either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’), or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fMRI was recorded at baseline and 3 weeks after the 2nd psilocybin dose, which was the final day of the 6-week daily capsule ingestion.  

Main Outcome(s) and Measure(s) Beck Depression Inventory and fMRI network modularity. 

Results Study 1: In 16 adults (mean age [SD], 42.8 [10.1] years, 4 [25%] female), psilocybin therapy was associated with markedly decreased BDI scores at 1 week (mean difference, -21; 95% CI=[-27.3, -14.7], P<.001) and 6 months (mean difference, -14.19; 95% CI=[-21.3, -7.1], P<.001). Decreased network modularity at one day post-treatment correlated with treatment response at 6 months (Pearson, 0.64; P=.01).

Results Study 2: In 43 adults (42.7 [10.5] years, 14 [33%] female), antidepressant effects favoured the psilocybin-arm at 2 (mean difference, -8.76; 95% CI=[-13.6, -3.9], P=.002) and 6 weeks (mean difference, -8.78; 95% CI=[-15.6, -2.0], P=.01). Specific to the psilocybin-arm, improvements at the 6-week primary endpoint correlated with decreased network modularity (Pearson, -0.42, P=.025). 

Conclusions and Relevance Consistent efficacy-related functional brain changes correlating with robust and reliable antidepressant effects across two studies suggest a candidate antidepressant mechanism for psilocybin therapy: decreased brain network modularity.”

Authors: Richard Daws, Christopher Timmerman, Bruna Giribaldi, James Sexton, Matthew Wall, David Erritzoe, Leor Roseman, David J. Nutt & Robin L. Carhart-Harris


An earlier study investigated the flattening of our brain on LSD. Not flat like a pancake, but with a flatter hierarchy and more possible states the brain can be in. This paper shows similar results for those treated with psilocybin.

The study analyzed fMRI data from the recent psilocybin versus escitalopram study (plus another study) and found that brains became less modular after treatment with psilocybin, but not escitalopram. This means that brain networks were more integrated, less sectioned off in distinct modules. This also correlated with the level of depressive symptoms six months later.

What does this study tell us?

  • Psilocybin leads to increases in cognitive flexibility, which correlates with lower depression scores
  • By analyzing the modularity of brains after psilocybin, we now have a more complete understanding of how it can help with depression
  • Specifically, psilocybin is able to resolve the abnormally constricted brain landscape that can be seen in depressed populations

As our picture of our brain on psychedelics becomes ever more complete, a robust finding emerges. The restrictive patterns that it’s stuck in, is stirred up and put settles back into a more ‘normal’ pattern.

Still, this is only a small part of the picture. The subjective interpretation of these patterns may be different from person to person (i.e. pain from sports or fatigue may look similar on brain scans). And without lifestyle changes, someone’s old patterns may soon creep back. Psychedelics, as we currently understand them, open a door, but a lot more research on therapeutic methods and support systems needs to be done to maximize the impact they can have.

Study details

Compounds studied

Topics studied

Study characteristics
Meta-Analysis Placebo-Controlled Active Placebo Double-Blind Open-Label Longitudinal Randomized



Authors associated with this publication with profiles on Blossom

Chris Timmermann
Chris Timmerman is a postdoc at Imperial College London. His research is mostly focussed on DMT.

David Nutt
David John Nutt is a great advocate for looking at drugs and their harm objectively and scientifically. This got him dismissed as ACMD (Advisory Council on the Misuse of Drugs) chairman.

Leor Roseman
Leor Roseman is a researcher at the Centre for Psychedelic Research, Imperial College London. His work focussed on psilocybin for depression, but is now related to peace-building through psychedelics.

David Erritzoe
David Erritzoe is the clinical director of the Centre for Psychedelic Research at Imperial College London. His work focuses on brain imaging (PET/(f)MRI).

Robin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.


Institutes associated with this publication

Imperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.

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