Patients treated with psilocybin with psychological support for treatment-resistant depression and a group of healthy controls receiving no treatment carried out a dynamic emotional faces task at two time points, separated by approximately 1 month. Prior to treatment with psilocybin, depressed patients in this trial were shown to have a global deficit in processing emotional faces as compared with healthy controls, as reflected in longer reaction times to identify all emotion types. Post-treatment, this between-group difference was remediated—with patients performing as well as controls. We observed a reaction time improvement post-treatment for all emotion types in depressed patients. In the control group, who were not given psilocybin, no retest improvement was observed. This suggests the improvement in the depressed group is not due to a learning effect but rather, may be related to their treatment.

We observed a significant positive correlation between faster RT to all emotions and improvements in anhedonia scores post-treatment. Anhedonia (lack of pleasure or interest in normally rewarding activities) is a key component of depression—and yet it is relatively unresponsive to standard antidepressant treatments (Lally et al. 2014). Both psilocybin with psychological support (Carhart-Harris et al. 2016) and ketamine (Lally et al. 2014) appear to facilitate an immediate improvement in anhedonia in depression. It has been suggested that ketamine’s fast-acting antidepressant effect may be due to large and immediate neurocognitive changes (Warren et al. 2015; Deakin et al. 2012; Abel et al. 2003) that subsequently allow fast relearning of patients’ social environments (Pringle et al. 2013). Our observed correlation suggests that improvements in facial processing relate to contemporaneous improvements in symptoms of anhedonia, in line with the neurocognitive model of antidepressant action (Warren et al. 2015). No correlations were observed between facial processing performance and the study’s primary measure of depressive symptoms (QIDS-16), suggesting that the post-treatment changes in emotional processing are selective to the symptom of anhedonia.

It has been recently proposed that psilocybin activates an emotion-releasing pathway mediated via the 5-HT2A receptor whilst SSRIs act on an emotion-moderating pathway mediated by postsynaptic 5-HT1AR signalling (Carhart-Harris and Goodwin 2017, Carhart-Harris and Nutt 2017). SSRIs have been associated with emotional moderation or ‘blunting’ (Price et al. 2009), whilst 15 out of 20 patients in the current trial endorsed a theme antithetical to this, labelled ‘emotional reconnection’ and ‘acceptance’ (Watts et al. 2017). Speculatively, the improved processing of all emotions, including negative ones, seen here post-treatment with psilocybin could be interpreted as consistent with emotional reconnection (Watts et al. 2017; Carhart-Harris et al. 2017). Indeed, recent research using the same sample as the current study with an additional two patients (n = 19) has shown increased amygdala response to fearful faces as compared with neutral faces after psilocybin (Roseman et al. 2017, Neuropsychopharmacology, under review). Reconnecting with one’s emotions and environment could account for the inter-related improvements in anhedonia and emotional processing post-psilocybin.

Focusing on group differences irrespective of treatment, an emotion × group interaction effect was observed, where across both time points combined, controls were faster at responding to neutral, angry, disgusted and fearful faces as compared with the depressed group. This finding is broadly consistent with the findings of Dalili et al.’s (2015) meta-analysis of 22 emotional face processing studies, which concluded that there was a global deficit for all basic emotions (anger, disgust, fear, happiness and surprise) except sadness in those with depression (Dalili et al. 2015). A key limitation here is that no three-way interaction was observed; thus, any interpretation of emotion-specific deficits across group and time should be treated with caution. Moreover, although age did not correlate with task performance, the two groups differed in age.

We also observed a time by emotion interaction effect, where reaction time for angry faces in both groups combined was significantly faster at the ‘post’ time point. This may reflect a differential learning effect on angry faces in this task that is insensitive to group, as we did not see a significant interaction with group on this measure.

There was a significant emotion by group interaction effect where across both time points combined, controls were more accurate at identifying angry faces. This was also reflected in a higher discrimination index (Pr) and a move to the ideal response bias (Br = 0.5) for angry faces in controls across both time points combined as compared to patients. This may reflect the fact that the emotional processing deficit in patients towards angry faces is resilient to change post-psilocybin. Although it should be noted that in this task, the faces become increasingly intense over time and thus easier to answer correctly. Indeed, following previous use of this task (Platt et al. 2010) reaction time should be the principal measurement from which to make conclusions.

In addition to emotional processing aptitude, performance on facial recognition tasks also involves a variety of cognitive functions such as selective attention, working memory and visual perception (Stuhrmann et al. 2011). Depressed patients are known to show cognitive impairments including both mnemonic and executive impairments (Austin et al. 2001) as well as perceptual deficits (Bschor et al. 2004; Bubl et al. 2010). Bearing this in mind, whether the depressed patients in our study showed a specific improvement in emotional processing or a more general cognitive improvement (e.g. executive function) or even perceptual (e.g. contrast sensitivity) ability remains to be resolved. To do so would require the inclusion of other behavioural paradigms in the trial, probing different aspects of affective and cognitive processing. In the future, it would be valuable to include other cognitive and perceptual tasks, in order to test whether psilocybin-treatment has a selective influence on emotional face processing or a more generalised remediating effect on affective and cognitive processing.

Strengths of the present study include its focus on a novel pharmacological mechanism associated with rapid improvement in treatment-resistant depression, pre/post-assessments in patients and controls, and a previously validated emotional processing task based on dynamic face morphing. There are several limitations to this study however, namely (1) controls were significantly younger than the patients and age has been found to affect emotional face recognition (Leime et al. 2013), (2) controls did not undergo a placebo treatment as they would in a randomised control trial (RCT), (3) additional cognitive tasks were not administered, (4) the sample size was modest, (5) SHAPS was not collected in controls and (6) the treatment group had psilocybin and psychological support whilst the control group had neither. There is some evidence that extended psychological intervention (16 sessions) may influence processing of facial affect in depression (Fu et al. 2008). Future studies should aim to determine whether psychological support and psilocybin have additive or synergistic effects on depressive symptoms and emotion recognition (Moss et al. 2016). Bearing in mind the ethical concerns of a psilocybin-only group in people with depression, this may be best achieved by comparing a minimum level of support with increasing doses of psychological intervention. In the future, studies could also incorporate an eye-tracking paradigm, as an intriguing explanation for reduced performance on emotional face recognition tasks may be aversion of gaze away from emotional stimuli. Many of these limitations were standard for an open-label pilot study such as it was, and can be addressed properly in future RCTs.

In conclusion, this study found generalised improvements in emotional face processing after psilocybin for treatment-resistant major depression that correlated with reduced anhedonia. Further studies are required to help determine whether the observed improvements are specific to emotion processing or more generalised, i.e. including improvements in perception and/or cognition; if the former, it will be important to address whether improvements in emotional processing are an integral component of the antidepressant mechanisms of this novel treatment modality (Carhart-Harris and Goodwin 2017).