Lea Julia Mertens, PhD candidate

Central Institute of Mental Health

Therapeutic Mechanisms of Psychedelic Drugs: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression



Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression (TRD), which correlated with treatment efficacy.


Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesized changed amygdala functional connectivity (FC), more precisely decreased amygdala – ventromedial prefrontal cortex (vmPFC) FC, during emotional face processing after treatment with psilocybin.


Psychophysiological interaction analyses were conducted on functional Magnetic Resonance Imaging (fMRI) data from a classic face/emotion perception task, with the bilateral amygdala and vmPFC time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week.


Results showed decreased vmPFC-right amygdala FC during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in FC between the amygdala and vmPFC to occipital-parietal cortices during face processing.


These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future placebo-controlled studies are needed to examine the replicability of the current findings.


Lea J. Mertens received her M.Sc. in Cognitive and Clinical Neuroscience with a specialization in Neuropsychology from Maastricht University. During her thesis internship at the Centre for Psychedelic Research, Imperial College London she i) was coordinator of the Global Psychedelic Survey ( and ii) wrote her Master’s thesis about functional connectivity changes after treatment with psilocybin in patients with treatment-resistant major depression, supervised by Dr. R. Carhart-Harris and Dr. M. Wall.

For her PhD she has joined the recently established Department of Molecular Neuroimaging, headed by Prof. Gerhard Gründer, at the Central Institute of Mental Health (CIMH) in Mannheim. Her main research interests lie in the therapeutic potential as well as biological and psychological mechanisms of psychoactive substances, with a particular focus on psychedelic drugs. She is currently involved in establishing a clinical trial investigating the therapeutic mechanisms of psilocybin in major depression using multiple neuroimaging techniques (e.g. PET-(f)MRI).



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