Depression is among the most widespread mental health disorders worldwide, typically characterised by persistent feelings of sadness, a lack of interest in daily activities and dysregulated sleep and/or eating habits. There is now a wide range of pharmacological treatments for depression, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants and atypical antidepressants.

In recent years, some research groups have been exploring the potential of alternative treatments for depression that rely on psychedelic compounds, such as psilocybin. Psilocybin is a compound naturally found in more than 100 species of mushrooms, which can influence the mood and perceptions of those who ingest it.

Researchers at Imperial College London's Centre for Psychedelic Research recently carried out a study aimed at better understanding the effects of psilocybin treatment on the processing of music and the experience of emotions, comparing them to those of escitalopram, a widely used SSRI.

Their findings, published in Molecular Psychiatry, suggest that compared to escitalopram, psilocybin tends to better preserve patients' emotional responsiveness, particularly during pleasurable experiences, such as listening to music.

"This paper stems from a larger clinical trial published in The New England Journal of Medicine, which compared the effects of psilocybin therapy and the SSRI escitalopram in treating depression," Rebecca Harding, first author of the paper, told Medical Xpress.

"While its primary focus was on clinical outcomes, we also wanted to explore how these treatments work, specifically, the mechanisms by which they affect emotional and reward processing. To do this, we collected a rich set of data, including self-report measures, behavioural responses, and functional MRI."

The main objective of the recent study by Harding and her colleagues was to understand how taking psilocybin or escitalopram affected how patients diagnosed with major depressive disorder (MDD) respond to music. The team decided to specifically focus on music because, compared to other tools used to assess changes after receiving treatment for depression, such as emotional face recognition tasks, music tends to unfold over time and thus better reflects real-world experiences that elicit emotional responses.

"This makes music an ideal tool for examining how treatments influence affective processing in a more ecologically valid way," explained Harding. "In our experiment, participants listened to a piece of music before and after a six-week treatment period. During this time, they received either two high doses of psilocybin (25 mg) with daily placebo pills, or two low doses of psilocybin (1 mg) with daily escitalopram."

Notably, the musical piece that participants were asked to listen to was annotated by professional musicians to highlight various features. These annotations pinpoint moments of musical surprise, unpredictable shifts in the melody or rhythm of the song that go against common mental predictions and are associated with pleasurable responses.

While the study participants were listening to the music track, Harding and her colleagues recorded their brain activity using functional magnetic resonance imaging (fMRI), a widely used imaging technique that works by detecting changes in blood flow. In their subsequent analyses, they specifically looked at changes in the participants' brain responses during the 'surprising' segments of the music they were listening to.

"We asked participants to continuously rate their emotional experience—specifically valence (how pleasant something feels) and arousal (how activating it is)—while listening to the music," said Harding.

"We also collected questionnaire data on symptoms like anhedonia (i.e., the reduced ability to feel pleasure) and their overall subjective emotional responses to music. Altogether, this allowed us to explore both the neural and subjective impact of the treatments on emotional and reward responsiveness in depression."

When they analysed the data collected in their experiment, the researchers observed significant differences between patients diagnosed with depression who were given psilocybin and those who were treated with escitalopram. First, they found that while the two treatments resulted in similar clinical improvements, psilocybin seemed to preserve or even enhance the study participants' emotional responsiveness, while escitalopram often blunted it.

"This has important implications for understanding how different antidepressant treatments affect the emotional lives of patients," said Harding. "Neuroimaging revealed that during musical surprises, psilocybin led to reduced activity in the ventromedial prefrontal cortex—a region involved in self-referential thinking and the processing of prediction errors—and increased activation in sensory regions.

"From a predictive processing perspective, these changes may reflect a reduction in the weighting of priors (which are often strong and rigid in depression) and a shift from an overactive internal narrative toward a more externally engaged mode of processing."

Essentially, the findings gathered by this research team suggest that compared to escitalopram and potentially other SSRIs, psilocybin could be more effective in restoring the ability of depressed patients to be emotionally moved by the world around them.

Further studies could help to validate these findings, potentially comparing the effects of psilocybin to those of other widely prescribed antidepressants. Meanwhile, Harding and her team at UCL are exploring the therapeutic potential of another psychedelic compound, called DMT, for the treatment of alcohol use disorder.

"In this new study, we're using naturalistic stimuli, specifically full-length films during fMRI, to investigate how psychedelics affect emotional and cognitive processing in real-world contexts," added Harding.

"I believe that naturalistic approaches in neuroimaging research, such as with film or music, are the next frontier in psychiatry. They allow us to better understand the moment-to-moment shifts in conscious experience that are often disrupted in mental illness."

--Ingrid Fadelli