How Does Psilocybin Affect The Brain?

Psychedelics, once considered fringe science, are now at the forefront of neuroscience because of their profound and unique effects on the brain. Among these substances, psilocybin, the active ingredient in magic mushrooms, has attracted the most significant attention among researchers, therapists and ordinary individuals for its potential therapeutic benefits.

The Science Behind Psilocybin’s Impact on the Brain

A recent groundbreaking study published in Nature explored how psilocybin affects brain function, shedding light on its potential therapeutic uses and the mechanisms behind its mind-altering effects. Using around 18 neuroimaging scans per participant, researchers tracked healthy adults before, during, and weeks after a psilocybin dose to examine both short-term and long-term brain changes.

How Psilocybin Changes Brain Connectivity

Psilocybin fundamentally changes how different parts of the brain communicate with each other, a process known as functional connectivity (FC).

Imagine FC as a network of conversations happening across a party dinner. Psilocybin doesn't just change the topics of these conversations; it reconfigures the entire network, making new connections and silencing others.

Psilocybin’s Effects on the Cerebral Cortex and Key Brain Regions

The study showed that psilocybin causes widespread changes in functional connectivity across the cerebral cortex, the brain's outer layer responsible for our thoughts, perception, and memory. These changes were most noticeable in the brain's association networks, which help integrate information from different senses and parts of the brain.

The subcortex, located beneath the cerebral cortex, also showed significant changes. The key areas affected included the thalamus (responsible for relaying sensory and motor signals), the basal ganglia (involved in movement and reward), the cerebellum (important for motor control), and the hippocampus (crucial for memory and emotional responses).

In particular, the anterior hippocampus showed strong disruptions in connectivity, which might help explain the profound emotional and psychological effects experienced by psilocybin users.

Psilocybin’s Role in Desynchronizing Brain Activity

Psilocybin also desynchronized brain activity, increasing what scientists call spatial entropy, a measure of randomness or disorder in brain activity. This desynchronization can be thought of as a reboot of the brain's operating system, potentially leading to new ways of thinking and perceiving the world.

Using the mystical experience questionnaire, researchers measured the intensity of participants' experiences. Higher mystical experience scores, which indicated more profound and awe-like experiences, were strongly linked to greater changes in functional connectivity. This suggests that the more the brain connectivity is altered, the more intense the psychedelic experience.

Comparing Psilocybin to ADHD medication

In order to compare psilocybin to another psychoactive compound, researchers also studied methylphenidate (MTP) or Ritalin, a stimulant used to treat ADHD.

MTP primarily affected the brain's sensorimotor systems, which are areas involved in processing sensory information and coordinating movement.

These changes were similar to the brain's day-to-day variability, likely due to MTP's arousal effects.

In contrast, psilocybin's impact was much more extensive and pronounced, especially in the Default Mode Network (DMN) which is a set of brain regions associated with self-referential thoughts and daydreaming.

Figure 1. This figure shows changes in brain functional connectivity (FC) under three conditions: after psilocybin intake, after methylphenidate intake, and during normal day-to-day variability. Panel (a) illustrates psilocybin's effects, with significant and widespread FC increases, especially in association networks, indicated by red areas. Panel (b) depicts methylphenidate's effects, showing more localized FC changes, primarily in sensorimotor regions. Panel (c) represents minimal, evenly distributed FC changes during normal day-to-day variability. Each condition is compared to baseline measurements taken before any drug intake to highlight the specific effects of psilocybin and methylphenidate on brain connectivity.

The Results

Psilocybin’s effects were stronger when people focused inwards

Psilocybin’s effects were found to be the strongest when participants focused inward, increasing brain desynchronization and intensifying mystical experiences such as feelings of unity and deep introspection.

On the contrary, engaging in simple tasks during the psilocybin experience moderated these effects, reducing brain desynchronization and functional connectivity changes.

This suggests that external engagement provides mental anchoring, helping manage the intensity of the experience.

The ability to moderate psilocybin's effects through task engagement highlights the importance of set and setting in psychedelic therapy. Therapists can use this knowledge to design sessions that optimise therapeutic outcomes, either by encouraging inward focus for deeper psychological exploration or by engaging in tasks to reduce anxiety and maintain control.

Understanding the context-dependent nature of psilocybin helps us to tailor the therapeutic approach to individual needs, enhancing the potential benefits of psychedelic-assisted therapy.

Figure 2. psilocybin’s disruptive effects decreased when people focused on a task.

The long-lasting effects of psilocybin on the brain

One of the most promising findings is the persistent changes in brain connectivity, particularly in the hippocampus, weeks after taking psilocybin.

This area showed a lasting decrease in connectivity with the DMN, which might underlie some of the long-term therapeutic benefits, such as reduced symptoms of depression and anxiety.

The noted persistent change in hippocampal-DMN connectivity suggests improved control over self-oriented thinking and memory. This shift might change how someone perceives their place and story in the world, promoting a more flexible and integrated brain network that fosters resilience against depressive and anxious states.

Such persistent effects distinguish psilocybin from traditional antidepressants, which often require continuous use to maintain benefits, highlighting its potential for lasting therapeutic impact.