A ‘magic’ moment in treating resistant depression?

Psilocybin is a prodrug of Psilocin , a classic psychedelic drug. It is a non selective serotonin agonist ( 2 A receptor). Psychedelics like LSD and Psilocybin were investigated as therapeutic agents in 1960s. Regulatory restrictions prevented assessing therapeutic potentials of these agents. An increasing interest in these possibilities has emerged in the past decade.

 A recent systematic review supported the idea that such agents can be of some benefit in those with anxiety and depression in the context of life threatening disorders (Reiche et al 2017).  If provided with psychological support ,psychedelics are useful in a range of psychiatric conditions (like end of life anxiety, OCD and some addictions). There is growing interest in psychedelic assisted psychotherapy as well. These agents also have anti-inflammatory properties which may also be of significance in treating many inflammatory disorders of neurological system. ( Nichols, 2017)

Robin L Carhart-Harris and colleagues from UCL  wanted to see how brain function changes when psilocybin is given to individuals with resistant depression.  This is the first study that documents  changes in resting-state brain blood flow and functional connectivity post-treatment with psilocybin for treatment-resistant depression. 19 patents with resistant depression participated in this. They  had f MRI before and after the intervention. Two doses of Psilocybin were given one week apart ( 10mg and 25 mg). 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.

Good antidepressant response with Psilocybin :

The mean depression score (QIDS-SR16) for the week prior to the pre-treatment scan was 16.9 ± 5.1, and for the day of the post-treatment scan, it was 8.8 ± 6.2 (change = −8.1 ± 6, p < 0.001).The mean QIDS-SR16 score at baseline (screening) was 18.9 ± 3, and for 5-weeks post-treatment, it was 10.9 ± 4.8 (change = −8 ± 5.1, p < 0.001). All showed some decrease in depressive symptoms at 1 week, with 12 meeting criteria for response . All but one patient showed some decrease in QIDS-SR16 score at week 5 (with one showing no change) and 47% met criteria for response (change = −9.2 ± 5.6 p < 0.001).

Brain correlates of improvement :

Increased RSFC was observed within the default-mode network (DMN) post-treatment.

Reduction in amygdala blood flow was associated with clinical improvement. Increased ventromedial prefrontal cortex & bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks. Decreased parahippocampal-prefrontal cortex RSFC was also predictive of treatment.

Patients scoring highest on ‘peak’ or ‘mystical’ experience had the greatest decreases in para hippocampal RSFC in limbic (e.g. bilateral amygdala) and DMN-related cortical regions.

Acute effects Vs post acute effects :

 Brain activity observed just one-day after a high dose psychedelic experience are very different to those found during the acute psychedelic state . Previous studies have shown decreased DMN integrity under psilocybin ( i.e. acute effect). In this study, increased DMN integrity was observed one-day post treatment with psilocybin. Psilocybin dysregulate cortical connectivity acutely,  and then create a state of enhanced connectivity ( ‘entropic’ brain state / ‘desegregation’= ‘ego dissolution/’openness’). In this regard, we can see some similarities with ECT, where DMN integrity is decreased acutely, followed by a strong normalisation effort resulting in increased coherence/ integrity post acutely. This later changes are related to improvements in mood.


This study is limited by its small sample size and absence of a control condition. Larger studies with placebo/ control conditions and longer follow up would be required to establish these exciting positive effects.

Summary of the article: 

Psilocybin for treatment-resistantdepression: fMRI-measured brain mechanisms.  Robin L Carhart-Harris et al. http://www.nature.com/scientific reports. 13 October 2017.


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