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

Psychedelics work differently than SSRIs and are hypothesized to treat the underlying disconnect with emotions, getting someone in touch with them again. This analysis of an open-label study (n=20) supports this argument with fMRI studies that showed increased amygdala responses to emotional stimuli.


“Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments’ therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.:

Authors: Leor Roseman, Lysia Demetriou, Matthew B. Wall, David J. Nutt & Robin L. Carhart-Harris


This paper is a follow-up/further analysis of Carhart-Harris and colleagues (2016).

  • Opposite amygdala response between psychedelics (increased) and SSRIs (decreased)
  • Hypothesized to show patients (with unipolar depression) reconnecting with their emotions
  • Right amygdala responses (after treatment) were predictive of clinical improvements at 1-week later

“Increased post-treatment BOLD responses were observed in the right amygdala for fearful (p=.001) and happy faces (p=.022), with a trend effect for neutral faces (p=.066). After correcting for 10 tests (5 contrasts X 2 ROIs), only the increased responses to fearful faces remained significant.”

The researchers note that all these changes are in the right amygdala and no significant change is found in the left amygdala.

The amygdala is a complex subcortical structure that is sensitive to emotional stimuli. Functional MRI studies of untreated clinically depressed patients have found amygdala hyper-sensitivity to negative emotional stimuli, and treatment with SSRIs has been found to attenuate this; both with chronic SSRI-use as well as early in treatment, prior to the appearance of clinical improvements.”

SSRIs seem to dampen these hyper-sensitive responses. They found that psychedelics didn’t have this effect, but in some cases even enhanced the responsitivity (fearful faces, right amygdala). What they challenge with this finding is the hypothesis that a lower response is indicative of lower depression scores. There may be different ways/methods to lowering depression scores, one in which amygdala responses are lowered (SSRIs, and affect in general is lowered), and another in which it’s raised (partly, psychedelics, connect with emotions).

“…SSRIs and related antidepressants have a more generalised muting influence on amygdala responses to emotionally salient stimuli. Relatedly, negative stimuli may be processed as especially salient, and thus be associated with greater amygdala responses which are subsequently hyper-sensitive to intervention-led change.

“Since the majority of patients reported improvements with the treatment, most answered in the affirmative and described a greater willingness to accept all emotions post-treatment (including negative ones). These effects were often contrasted with those of their previous depression treatments which they described as working to reinforce emotional avoidance and disconnection.”

This further supports the above point of connecting patients to their emotions.

In the final part of the discussion, the authors point out various limitations and future directions for research. These include suggestions for more fMRI moments (during, 1 week after, 1 month after) and comparisons with other subject groups (e.g. healthy normals) and with a placebo.

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