How Does Psilocybin Work in the Brain?

How Psilocybin Affects Overall Brain Connectivity

The Default Mode Network Explained

You may think that specific areas of the brain carry out specific tasks, but through brain imaging research, we’ve discovered that the brain operates in “networks,” calling on multiple different brain regions to work together to achieve various tasks.

These tasks can be anything from decision-making, introspection, and emotional-processing, to directing attention and retrieving memories, and can require varying levels of connectivity, which varies over time in response to fluctuations in emotional and cognitive states (Lettieri et al., 2021).

The Default Mode Network (DMN) is most commonly referred to when discussing psychedelics and our brain. It’s characterized by the connectivity of certain regions of our brain, namely the anterior medial frontal cortex, ventral medial prefrontal cortex, posterior cingulate cortex, precuneus, inferior parietal lobule, and middle temporal gyrus that come together to achieve tasks like:

• Self-reflection/Daydreaming

• Emotional processing

• Social interaction

• Mental exploration

• Construction of personal narratives (Azarias et al., 2025)

Psilocybin, Serotonin & the Default Mode Network

Psilocybin is a psychoactive compound found in “magic mushrooms” that benefits our body and mind in a way we’re just beginning to understand. As any good mycologist knows, the benefits of medicinal mushrooms are far reaching, and not just the psychedelic ones.

When ingested, psilocybin turns into a related compound called psilocin, which is a serotonin 5‐HT 2A receptor (5‐HT2AR) agonist, which means it mimics the serotonin that’s found in our body.

Serotonin wears many hats, from regulating our nervous system to aiding in digestion, and its receptors are found all over the body, but it’s most widely known for being the “happy chemical” in our brain, responsible for emotional stability and satisfaction.

The 5‐HT 2A receptor is what “holds” or “activates” serotonin and is concentrated in our brain matter (the cerebral cortex), more specifically in the areas that handle decision making, social behavior and personality, but also in the visual cortex, responsible for processing visual information.

The default mode network happens to be saturated in these 5‐HT 2A receptors. Our natural serotonin acts as a stabilizer for this network, helping it maintain a coherent “narrative” of who you are.

However, in many people with depression or anxiety, the DMN becomes overactive or “rigid.” It gets stuck in a loop of rumination—the same negative thoughts about the self, over and over (Zhou et al., 2020).

This is why disrupting these rigid thought patterns by flooding the serotonin receptors with psilocin can cause changes in our thoughts and behaviors for the better, especially with the increase in neuroplasticity, meaning the brain’s heightened ability to change, adapt or rewire.

Recommended Reading: Psychedelics and Serotonin – How Mind-Altering Substances Interact with the Brain’s Chemical System

What Siegel et al. (2024) Discovered in Psilocybin Desynchronizes the Brain

Remember in the beginning of the article where we mentioned Siegel and his team of investigators? Participants in this study were either given psilocybin, or Ritalin which was used as a control.

Up to 18 fMRI brain scans were taken of participants’ brain activity before, during and after taking psilocybin, which ensured they collected as much data as possible.

They were able to show how functional connectivity in the brain was affected by psilocybin, 3 times greater than Ritalin in fact. The greater the change in functional connectivity, the more intense the experience was reported to be. 

Their fMRI data revealed three key things:

• Massive Desynchronization: Psilocybin, mimicking serotonin, floods those 5-HT2A​ receptors, causing the DMN to lose its usual rhythm. This disruption of the usual thought patterns can be seen as the biological explanation for “ego dissolution or ego death“—that feeling of the “self” disappearing.
• Increased Global Connectivity: While the DMN stops talking to itself, the rest of the brain starts talking to everyone. Parts of the brain that usually never communicate (like the visual cortex and the emotional centers) suddenly form new, temporary links. This is why people see colors when they hear music (synesthesia) or have sudden, “out of the box” epiphanies.
• The “Afterglow” Reset: Most importantly, the study found that even after the drug left the system, the DMN didn’t just snap back to its old, rigid ways. Brain patterns remained altered for weeks. 

Siegel et al. suggests that psilocybin acts like a “system reboot.” By temporarily breaking the DMN’s grip on your perception, it creates a “window of neuroplasticity,”  where the brain can rewire itself into a healthier, less ruminative pattern.

The Afterglow Effect Explained

We already knew that something special happens in our brain for a few weeks following a psilocybin experience, and it’s been coined the afterglow effect.

Qualitatively, it’s marked by subacute feelings of heightened mood, increased creativity, increased cognitive function, and potential increase in cognitive performance, and is also seen with other psychedelic substances, albeit varied manifestations (Basedow et al., 2024).

On the neurobiology side, it’s marked by the increased neuroplasticity following a psilocybin experience, but specifically a decrease in functional connectivity between the DMN and anterior hippocampus, part of our memory center, a persistent change that lasted for weeks (Siegel et al., 2024).

The anterior hippocampus is particularly integrated into networks supporting emotional and contextual processing, and plays a distinct role in processing and moderating feelings, especially fear, anxiety and stress.

The anterior hippocampus also contributes to forming new memories particularly linked to emotional information. It’s even active when we reexperience past events, like replaying memories in our head.

As we unravel the relationship between psilocybin, the DMN and the anterior hippocampus, we can see how a depressed brain, one stuck in the same negative thought patterns, may benefit from separating their emotional memory center and their “self” creator (the DMN) for a little while.

This break in connectivity may allow patients to process traumatic or painful memories without the usual “fight or flight” response, revisiting past events in a way that isn’t retraumatizing, as observers rather than victims.

Traditional antidepressants (SSRIs) often work by dulling emotions to make life manageable. Psilocybin appears to do the opposite—it increases the brain’s ability to learn and adapt.

This makes the weeks following an experience a “fertile window” for integration and therapy, where new, healthier habits and thought patterns can actually take root and physically wire themselves into the brain.

How Psilocybin Affects the Brain on a Cellular Level

The most striking cellular effect is that psilocybin physically changes the shape of your neurons. A landmark 2021 in vivo animal research study by Shao et al. showed that a single dose of psilocybin increases the density and size of dendritic spines.

In a healthy brain, these spines facilitate the flow of information. However, chronic stress and depression can cause them to wither away, effectively “pruning” the brain’s ability to communicate.

Researchers used Thy1GFP transgenic mice, which have been genetically engineered to have glow-in-the-dark neurons, to observe the biological processes happening in the brain.

By using chronic two-photon microscopy to look through a “cranial window,” they were able to take pictures of individual neurons and their dendritic spines repeatedly for a month.

Remarkably, researchers saw a 10% increase in new spines within just 24 hours of psilocybin administration, suggesting a rapid physical repair of these neural pathways.

This leads us to a process called synaptogenesis: the formation of the actual synapses (the functional junctions) between neurons. While this process is most active during early brain development and slows down as we age, it remains the key to changing our thoughts and behavior.

In 2023, Song et al. theorized that psilocybin could potentially re-awaken this developmental process, allowing the adult brain to form new connections once again.

Lo and behold, this theory was validated in 2025, when Vella et al. discovered that psilocybin does, in fact, induce the formation of new, functional synapses.

Psilocybin has also been shown to affect gene-expression, particularly in “early-response genes” like c-Fos and Arc. It actually turns these genes on, causing them to signal the cell to reorganize its structure, which makes it more flexible and capable of learning (Shao et al., 2021).

Finally, the activation of serotonin 5‐HT2A receptors via psilocybin kicks off a chemical cascade, leading to the release of Brain-Derived Neurotrophic Factor (BDNF).

BDNF is a protein that basically acts as a fertilizer for your brain, supporting the survival of existing neurons while encouraging the growth of new ones. Recent research suggests that psilocybin may bind to TrkB receptors used by BDNF, helping to trigger neuroplasticity faster. (Moliner et al., 2023).

It’s been commonly thought that psilocybin only affects neurons that have 5-HT2A receptors, but by using genetically modified mice that could have their 5-HT2A receptors “turned off,” Ekins et al., 2025 discovered that psychedelics actually trigger neuroplasticity in neurons without 5-HT2A receptors.

This is an important finding because it showed that the retrosplenial cortex (RSG), an area devoid of any 5-HT2A receptors, majorly benefits from the synthetic form of psilocybin, and is one of the first areas of the brain to deteriorate in Alzheimer’s diagnoses. It also shows we have far more to learn!

When you look at all the tasks psilocybin is completing in your head while you’re seeing fractals and meeting god, you have an extremely compelling case for psilocybin as a tool for profound neurological change. 

How Our Attention Can Control the Effects of Psilocybin

Similar to how psilocybin affects our brain, our brain can affect how psilocybin works within it. In the same study mentioned above, Siegel et al. (2024), an interesting relationship was discovered.

Researchers found that by focusing participants on a task (matching an image or word to a target), it caused brain activity to revert back to more synchronized patterns, effectively working as a “trip killer” by turning your focus to the outside world.

This means that if you’ve ever watched TV on mushrooms, you may have been “killing” your trip, or at least limiting its potential. It also poses an interesting question for future research in managing difficult experiences. 

Why it Matters to Those With Mental Health Conditions

With the dysregulation of the DMN leading to neuroplasticity, and all the other hidden tasks psilocybin performs within the brain, it creates a unique opportunity to heal, given the right support.

Researchers investigating the effects of psilocybin on treatment-resistant depression found that a strong relationship between the therapist and study participant was more important to lasting change than the act of ingesting psilocybin, but together, the effects magnify (Davis et al., 2020).

As we wrap up this article, we want something to stick with you. Psilocybin can do a lot, but healing cannot be done in an echo chamber. Whether it’s a friend, a group of likeminded people, or a trusted, professional facilitator, community is the key to true healing.

Long-lasting Psychological Change

The changes seen from psychedelics, like shifts in worldview or relief from depression, aren’t just for the duration of the trip. Studies have continuously shown positive changes in how people perceive themselves and the world around them, allowing them to emerge with a renewed sense of openness and curiosity.

The Center for Psychedelic and Consciousness Research at Johns Hopkins University has been pioneering the revival of psychedelic research since the War on Drugs killed any psychedelic research after the 1970s.

Back in 2006, they were the first in the 21st century to administer a classic psychedelic (psilocybin) to drug naïve participants. In this study, all participants had a clinical diagnosis of treatment-resistant depression.

Aside from 67% of participants reporting profound experiences rated as among the top 5 most meaningful experiences of their lifetime, it showed real promise as a tool to relieve longstanding depression. 

A single psilocybin session led to positive changes in mood, attitude, and behavior for 14 months (possibly longer), with 64% indicating the experience increased well-being or life-satisfaction (Griffiths, et al., 2006).

The same researchers from the study that showed the importance of a therapist-patient relationship, checked in on their participants 5 years later, and what they found was even more impressive than the last results.

Lead investigator, Alan Davis, stated, “we found that 67% were in remission at five years compared to 58% at one year. We also saw that across the board, anxiety, depression, global functioning, self-reported depression, all of these measures were showing the same signal of continued improvement up to five years later.”

For decades, the “chemical imbalance” theory dominated our approach to mental health, but the research from Siegel, Shao, and others suggests we should be looking at connectivity and flexibility instead.

This research promises an exciting new paradigm into the future, one that uses research-backed evidence to create healing modalities that have the potential to change the entire trajectory of humanity by actually working to heal us, both individually and collectively.