Psilocybin and standard antidepressants both shift the brain away from negative biases

Psilocybin and standard antidepressants both reduce the brain’s tendency to view the world through a negative lens. The findings suggest both drugs might relieve depression by shifting how the brain processes emotional information, though they may achieve this through different timelines. The research was published in Translational Psychiatry.

Depression involves more than just a persistently low mood. It affects how people perceive reality on a subconscious level. People with major depressive disorder often exhibit a negative affective bias, meaning they tend to interpret ambiguous or even positive social cues as negative. They might look at a neutral facial expression and perceive anger or sadness.

According to cognitive models of depression, this skewed perception plays a fundamental role in maintaining the illness. When people constantly interpret their social environment as hostile or rejecting, it reinforces their depressed mood. Breaking this cycle is a primary goal of psychiatric intervention.

Traditional treatments like selective serotonin reuptake inhibitors, known as SSRIs, aim to correct this imbalance. Medications such as escitalopram often take several weeks to produce noticeable improvements in a patient’s mood. Researchers believe this delay happens because the drugs first shift the brain’s emotional processing bias. Patients then need time to interact with their environment and experience positive social feedback before their overall mood lifts.

In recent years, psychiatric researchers have explored psychedelic compounds as alternative treatments for depression. Psilocybin is the active hallucinogenic ingredient in magic mushrooms. Clinical trials indicate that psilocybin can alleviate depressive symptoms much faster than traditional daily pills, but it remains unknown exactly how the compound changes cognitive functions to achieve this rapid relief.

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A team led by Marieke A. G. Martens, a psychiatry researcher at the University of Oxford, designed a study to compare the cognitive effects of both drugs. The team included Robin Carhart-Harris and Catherine J. Harmer, among other researchers. They wanted to see if psilocybin works through the same emotional processing pathways as conventional antidepressants.

The study involved 59 patients diagnosed with long-standing, moderate-to-severe depression. The researchers randomly assigned these participants into two separate groups for a six-week trial. They conducted the study under double-blind conditions, meaning neither the patients nor the clinicians knew which full treatment protocol any individual received.

The first group received two 25-milligram doses of psilocybin spaced three weeks apart. These patients also took an inactive placebo pill every day for the six weeks. The second group received a daily dose of the SSRI escitalopram for the entire six-week period. To maintain the blind design, this second group also received two tiny one-milligram doses of psilocybin, which acted as a placebo during the dosing sessions.

Medication was only one component of the treatment protocol. Both groups received identical psychological support throughout the trial. This included preparatory sessions before receiving the psychedelic doses. Therapists also provided integration sessions afterward to help patients process their hallucinogenic experiences.

To measure emotional processing, the researchers used a computer-based assessment called the Facial Expression Recognition Task. Participants completed this task at the beginning of the trial and again at the six-week mark. During the test, patients viewed images of human faces flashing on a screen for half a second.

The faces displayed one of six basic emotions: anger, disgust, fear, happiness, sadness, or surprise. The researchers morphed these images to display varying intensities of emotion, ranging from completely neutral to full intensity. Participants had to identify the emotion shown on each face as quickly and accurately as possible using a keyboard.

Before the treatments began, the participants displayed a measurable negative bias, accurately identifying negative emotions but struggling with positive ones. After six weeks, both treatment groups showed a reduction in this negative bias. The differences between the psilocybin and escitalopram groups were not statistically significant.

Across both groups, participants became less accurate at recognizing negative emotions compared to their baseline scores. They also made fewer errors misclassifying faces as negative. Reaction times for identifying negative and positive emotions improved after the treatments. The researchers noted that patients recognized positive emotions even faster than negative ones at the end of the trial.

Previous brain imaging studies on these same patients showed that the two drugs had different physical effects on the brain. Escitalopram reduced activity in the amygdala, an area involved in processing fear and emotion, when patients viewed faces. Psilocybin did not produce this same dampening effect on amygdala activity. Despite these neurological differences, the behavioral outcomes on the emotional recognition task were remarkably similar.

The researchers then looked for links between these cognitive changes and overall depression symptoms. They measured depression severity using a standard self-report questionnaire at the six-week mark. At this concurrent time point, the reduction in negative emotional bias did not correlate with a drop in depression scores for either group.

The team followed up with the patients one month after the trial ended, at the ten-week mark. For the patients who took escitalopram, a decrease in misclassifying positive faces as negative at six weeks predicted lower depression scores at ten weeks. This aligns with the theory that SSRIs slowly improve mood as patients experience the world through a less negative lens.

This longitudinal relationship did not appear in the psilocybin group. The reduction in negative bias at six weeks did not predict better depression scores at ten weeks for these patients. The lack of correlation suggests that while psilocybin does alter emotional processing, its fast-acting antidepressant effects might rely on other psychological or neurological mechanisms.

The researchers noted several limitations to their experimental design. The trial did not include a pure inactive placebo group that received no active medication at all. Without a strict control group, it is difficult to completely separate the chemical effects of the drugs from the psychological support provided during the trial.

There was likely an inadvertent sample bias among the volunteers. Patients who sign up for clinical trials involving psychedelics often hold a strong preference for receiving psilocybin over traditional daily medications. This preference could influence how they respond to the respective treatments and how they report their symptoms.

Future studies will need to incorporate active placebo groups to better manage the blinding process in psychedelic research. Researchers also plan to measure emotional processing much earlier in the treatment timeline. Assessing patients within days of taking psilocybin could reveal how quickly these cognitive shifts occur compared to traditional medications.

Both treatments successfully shifted how patients interpreted emotional information, highlighting a shared cognitive outcome. The exact pathway from altered perception to mood improvement remains an active area of investigation. The study, “Negative affective bias in depression following treatment with psilocybin or escitalopram – a secondary analysis from a randomized trial,” was authored by Marieke A. G. Martens, Bruna Giribaldi Cunha, David Erritzoe, David Nutt, Robin Carhart-Harris, and Catherine J. Harmer.