Neuroscience - Psilocybin's potential for profound change

Introduction

Psilocybin is a psychoactive compound found in certain types of mushrooms naturally occurring on every continent on our planet.

The substance has a long history of use in spiritual ceremonies, festivals, and modern subcultures.

The effects of Psilocybin are altered perceptions of sights, sounds, time and space and an overall profoundly changed sense of reality that can feel frightening or overwhelming for some individuals.

In recent years, studies have suggested that Psilocybin and related analogs may hold therapeutic potential in treating a range of mental health conditions, including addiction, depression, anxiety, and PTSD.

In this post, I will give a brief overview to illustrate why researchers are increasingly fascinated by the hidden potential of so-called “magic mushrooms”.

Desynchronizing the sense of self

Normally, each person’s functional brain network is as unique as a fingerprint. Under the influence of Psilocybin, however, these networks become disrupted and less individualized. If our brain activity were measured with an fMRI scanner(a tool that measures brain activity), it would actually be easier to tell you apart from your own sober self than to tell you and me apart while we are both on Psilocybin.

This effect is especially pronounced in the so-called Default Mode Network (DMN) — a characteristic pattern of brain activity that emerges when the mind is at rest, wandering, or not focused on any specific task. Your DMN activity is normally highly individual, but on Psilocybin it becomes far less distinct, blending into a more uniform state that looks surprisingly similar across different people.

But how could this help individuals to overcome addiction and other mental illnesses?

The answer lies in the way Psilocybin disrupts rigid patterns of brain connectivity. Imagine a person with severe trauma or recurrent symptoms of depression and negative self-view. Over time, this person’s brain constructs a “self” that constantly guides thoughts and behaviors along the same painful loops, reinforcing despair.

Neuroimaging studies, for example, have shown that people with depression often display heightened functional connectivity between the hippocampus (a structure involved in memory) and the Default Mode Network (DMN). This tight coupling can trap individuals in cycles of rumination and self-focus. Psilocybin appears to desynchronize such connections, loosening the grip of the DMN, altering the sense of self, and creating a window for increased neuroplasticity. Within this state, the belief that change is possible can emerge.

Importantly, this desynchronization is not limited to the acute psychedelic experience — it has been observed to persist for days or even weeks after a single session, although not permanently. This extended window may be what gives therapeutic interventions their unique power when combined with Psilocybin.

The science behind it 1 : acute effects

The study I looked at shows that the brain’s functional connectivity (FC) — in simpler terms, the intensity of communication between brain areas — is significantly altered under Psilocybin, and some of those changes last well beyond the trip itself.

Here’s the primary source I analyzed :
https://www.nature.com/articles/s41586-024-07624-5/figures/1

6-Step Explanation how to read the graphic in the link above(1a, 1b, 1c)

1. Signal source
   fMRI measures blood oxygenation (BOLD), an indirect marker of neural activity in different brain regions.

2. Functional connectivity (FC)
   FC is calculated as the correlation between the time series of different brain regions. Correlations range from –1 to +1, but in practice most lie between 0.0 and 0.5.

3. From matrix to vector
   All pairwise correlations are flattened into a single vector, which represents the brain’s “connectivity fingerprint” at one state (e.g., sober or on Psilocybin).

4. Euclidean distance
   The distance between two states (two FC vectors) is the square root of the sum of squared differences across all connections.

5. Normalization
   Before comparing distances, FC values are often z-scored or otherwise normalized. This keeps the values in a compact, dimensionless range.

6. Interpreting the scale
   Because individual FC values are small and highly correlated, the resulting Euclidean distances rarely exceed ~0.5:

   • ~0.1 → very similar states
   • ~0.5 → substantially reorganized network

   The key insight: it’s the relative difference that matters (sober vs. Psilocybin vs. between subjects), not the absolute number itself.

Figure 1c–1f illustrates how the subjective experience can vary dramatically from session to session, as measured by the MEQ-30 (Mystical Experience Questionnaire), a tool that quantifies the intensity of psychedelic effects. This variability highlights why any therapeutic use of Psilocybin must be nuanced, professionally guided, and embedded in repeated, controlled environments.

Self-medicating with untested substances in uncontrolled settings is not only ineffective but potentially dangerous. Professional medical assessment and structured therapeutic frameworks are essential—even to test the theory safely.

Lasting change is always a process, never a one-shot deal.

The science behind it 2 : Local and global desynchronization

Watch this primary source as you read:

https://www.nature.com/articles/s41586-024-07624-5/figures/3

Figure 3a compares resting-state fMRI signals under Psilocybin versus methylphenidate (Ritalin). Psilocybin clearly increases spatial complexity—also called entropy, or more simply, randomness—both locally and globally. This is quantified in panels 3b and 3c, which introduce the NGSC (Normalized Global Spatial Complexity) measure.

Panels 3d and 3e visualize how NGSC changes are not limited to Psilocybin: LSD produces similar effects, suggesting a robust mechanism shared across multiple psychedelic substances.

Finally, panel 3f links these effects to pharmacology. Psilocybin is metabolized into Psilocin, which alters functional connectivity most strongly in brain regions rich in 5-HT2A receptors. These receptors are enriched in association cortex, including DMN regions, *“frequently associated with neuropsychiatric disorders34,35,87,88,89,90,91, and in a region of the anterior and middle hippocampus associated with the self29,92 and the present moment93.” ¹

The science behind it 3 : Persistent effects on hippocampal–cortical FC

Watch this primary source as you read:
https://www.nature.com/articles/s41586-024-07624-5/figures/5

This part of the study demonstrates that changes in hippocampal–cortical functional connectivity (FC) can persist for up to three weeks, before gradually returning to baseline. This is clearly visible in Figure 5a, where connectivity reductions remain weeks after the initial session.

Figure 5c provides an individual example, contrasting pre- and post-psilocybin scans and illustrating the persistent drop in connectivity with the Default Mode Network (DMN).

Conclusion

Psilocybin desynchronizes the brain on both a local and global scale, with the strongest effects observed during the initial intake and measurable alterations persisting for around three weeks. This change in communication—especially between the hippocampus and cortical regions—may open a temporary window for profound change, enabling individuals struggling with mental illnesses to experience relief and create lasting therapeutic progress.

Maybe in a few years (altered to produce fewer hallucinogenic effects while retaining the therapeutic benefits):

This isn’t pure speculation—several biotech companies are already working on non-hallucinogenic 5-HT2A agonists that aim to provide the neuroplasticity boost without the full psychedelic trip. If successful, such compounds could make psychedelic-inspired therapy more accessible in clinical settings.

Further reading

https://nida.nih.gov/research-topics/psilocybin-magic-mushrooms#effects-psilocybin https://www.nature.com/articles/s41586-024-07624-5 https://medicine.washu.edu/news/mushrooms-generate-psychedelic-experience-by-disrupting-brain-network/

1. Nature (2024). Psilocybin desynchronizes the human brain. https://www.nature.com/articles/s41586-024-07624-5 ↩︎