Psilocybin: How does it work?

Psilocybin, the psychoactive compound found in over 200 species of "magic mushrooms," has rapidly moved from counterculture curiosity to the frontier of mental health research. Yet, a question remains: how does psilocybin actually work inside the brain? What makes a single dose capable of producing effects that last for weeks or even months? The answer lies in a remarkable chain of events: a chemical conversion, a flood of serotonin receptor activity, the temporary dissolution of rigid brain networks, and a surge of neuroplasticity that might just rewire the brain.

Psilocybin Is a Prodrug: The Conversion to Psilocin

You might not know this, but psilocybin itself is not actually the compound that produces psychedelic effects. It is a "prodrug," meaning the body must convert it into its active form before it can do anything. Once ingested, psilocybin is rapidly transforms it into psilocin.

This conversion happens primarily in the intestines and liver, with psilocin becoming detectable in the bloodstream within 20 to 40 minutes of ingestion. Psilocin is the molecule that crosses the blood-brain barrier and produces every effect associated with a psychedelic mushroom experience.

Once in the body, psilocin is eventually broken down through several metabolic pathways. The relatively straightforward metabolism means that significant drug interactions with common medications are unlikely, though research in this area is still limited. Take precautions.

How Psilocin Interacts With Serotonin Receptors

The reason psilocin has such powerful effects is its structural similarity to serotonin, one of the brain's most important neurotransmitters. Serotonin regulates mood, cognition, perception, and emotional processing. Since psilocin's chemical structure closely resembles serotonin, it can bind to and activate serotonin receptors.

The Central Role of the 5-HT2A Receptor

The 5-HT2A receptor is considered the primary target responsible for psilocybin's psychedelic effects. When researchers block this receptor with an antagonist drug called ketanserin, the perception-altering, cognition-shifting, and emotion-altering effects of psilocybin are almost entirely prevented. Clinical studies confirm that psilocybin acts as a partial agonist at 5-HT2A receptors, meaning it activates them but not to the full extent that the body's natural serotonin would.

These receptors are densely concentrated in the cerebral cortex, particularly in the prefrontal cortex (PFC) and association cortices the region responsible for high-order thinking, self-reflection, decision-making, and perception. Importantly, 5-HT2A receptors sit on two key cell types:

1. Pyramidal neurons: the main excitatory "computational units" of the cortex
2. GABAergic interneurons: inhibitory neurons that modulate brain activity

This dual activation creates a complex cascade. Psilocin stimulates glutamate release (excitatory signaling) from pyramidal neurons while simultaneously triggering GABA release (inhibitory signaling) from interneurons. The net result is a temporary disruption of normal brain communication patterns.

The 5-HT1A Receptor's Supporting Role

Psilocin also acts as a partial agonist at the 5-HT1A receptor, though with lower affinity. Recent research from Penn Medicine found that both 5-HT2A and 5-HT1A receptors contribute to psilocybin's effects, particularly in pain and mood regulation. The researchers described psilocybin as acting "more like a dimmer switch" than an on/off toggle.

What Is the Default Mode Network?

One of the most significant discoveries in psychedelic neuroscience is psilocybin's effect on the Default Mode Network (DMN). The DMN includes the prefrontal cortex, posterior cingulate cortex (PCC), hippocampus, and several association cortices. This network is responsible for:

1. The sense of self and identity
2. Rumination and internal monologue
3. Perception of time and space
4. Autobiographical memory retrieval

In conditions like depression, the DMN often becomes hyperactive, trapping people in rigid, repetitive patterns of negative self-referential thinking.

How Psilocybin Disrupts the DMN

A landmark 2024 study published in Nature, led by researchers at Washington University School of Medicine, used precision functional brain mapping to track psilocybin's effects in healthy adults. The findings were striking:

1. Psilocybin massively disrupted functional connectivity across the brain, with changes more than three times greater than those caused by methylphenidate (Ritalin)
2. The largest disruptions occurred within the default mode network
3. Brain networks became desynchronized, activity within networks lost its usual coordination, and the boundaries between normally distinct networks dissolved
4. Individual brains became so disrupted that participants could no longer be identified by their unique brain signatures until the drug wore off

Why DMN Disruption Matters for Therapy

The temporary breakdown of the DMN is believed to be the key mechanism behind psilocybin's therapeutic potential. By desynchronizing the network responsible for rigid self-referential thinking, psilocybin may open a window where the brain can form new patterns of thought and connection.

This aligns with the influential REBUS model (Relaxed Beliefs Under Psychedelics), which proposes that psychedelics reduce the brain's reliance on top-down predictions and prior beliefs, allowing more flexible, bottom-up information processing to emerge. For someone trapped in depressive rumination, this "reset" may be exactly what breaks the cycle.

Rapid Growth of New Brain Connections

Preclinical research has shown that psilocybin promotes:

A 10-fold increase in dendritic spine density in the mouse prefrontal cortex, with changes persisting for at least 34 days

Increased presynaptic density in the hippocampus and prefrontal cortex of pigs, lasting at least 7 days post-dose

Neurogenesis (the birth of new neurons) in the hippocampus at low doses

These structural changes are mediated by a specific molecular pathway: psilocin's activation of 5-HT2A receptors triggers glutamate release, which stimulates AMPA and NMDA receptors, leading to increased production of brain-derived neurotrophic factor (BDNF) and activation of the TrkB-mTOR signaling pathway. This cascade promotes the growth of new synapses, dendritic branching, and spine formation, essentially building new hardware in the brain.

Lasting Changes After the Trip Ends

The NIH-funded Washington University study found that while most brain changes returned to normal within days of taking psilocybin, one key change persisted: a reduction in functional connectivity between the default mode network and the hippocampus lasted for at least three weeks. This persistent change may reflect the lasting reorganization of circuits involved in self-perception and memory. This potentially explaining why therapeutic benefits endure long after the drug has left the body.

A 2025 study from Penn Medicine published in Nature Neuroscience further identified the anterior cingulate cortex (ACC) as a critical hub where psilocybin calms hyperactive neurons associated with both chronic pain and depression. The researchers found that psilocin injected directly into the ACC provided the same pain relief and mood improvements as systemic psilocybin administration, pinpointing this brain region as a key site of action.

Therapeutic Applications

The growing understanding of how psilocybin works has fueled an explosion of clinical research into its therapeutic applications.

Depression

Psilocybin-assisted therapy has shown remarkable results for both major depressive disorder (MDD) and treatment-resistant depression (TRD). Johns Hopkins research demonstrated that psilocybin's antidepressant effects can last at least 12 months in certain patients after just two doses combined with supportive psychotherapy. In February 2026, Compass Pathways announced that its synthetic psilocybin (COMP360) successfully achieved its primary endpoint in a second Phase 3 clinical trial for TRD, with 39% of participants in the 25mg group showing clinically meaningful improvement sustained for six weeks.

Anxiety and End-of-Life Distress

Trials at Johns Hopkins and NYU demonstrated that psilocybin-assisted therapy helped terminally ill patients find emotional peace and significantly reduced their fear of death. Meta-analyses show psilocybin superior to placebo for treating anxiety at multiple time points after treatment.

Substance Use Disorders

Early studies suggest psilocybin therapy can support recovery from alcohol dependence and tobacco addiction. In smoking cessation research, participants showed significant abstinence after psilocybin sessions combined with cognitive behavioral therapy, with no significant adverse events.

OCD, PTSD, and Beyond

Research from Yale shows encouraging results for OCD, with 89% of patients experiencing symptom reduction at the 24-hour mark. PTSD research, particularly with veteran populations, is ongoing with encouraging early data.

Psilocybin vs. Traditional Antidepressants

A Phase 2 clinical trial comparing psilocybin to escitalopram found that both reduced depression scores, but secondary outcomes favored psilocybin, and it required only two doses versus daily medication.​

Safety Considerations

Psilocybin is considered physiologically safe with no risk of addiction and no lethal overdose threshold in humans. However, important safety considerations include:

1. Psychological risks: Psilocybin can induce anxiety, panic, confusion, or paranoia, particularly at high doses or in uncontrolled settings
2. Contraindications: People with a personal or family history of psychotic disorders (such as schizophrenia or bipolar disorder) are at risk and are excluded from clinical trials
3. Physical side effects: Mild, transient effects include headache (~50%), nausea (~36%), and slight elevation of heart rate and blood pressure
4. Set and setting matter: Therapeutic outcomes are heavily influenced by the psychological mindset of the user and the physical environment during the experience

Clinical researchers strongly caution against self-medicating with psilocybin outside of supervised, controlled settings.

The Bottom Line

The science of how psilocybin works has advanced dramatically. The chain from prodrug conversion, to serotonin receptor activation, to default mode network disruption, to lasting neuroplastic changes represents one of the most compelling therapeutic mechanisms discovered in modern psychiatry.

With Phase 3 clinical trials achieving their primary endpoints and FDA review potentially on the horizon, the path from ancient mushroom ceremony to evidence-based medicine is becoming increasingly clear. For those seeking relief from treatment-resistant depression, anxiety, addiction, or chronic pain, psilocybin offers a fundamentally different approach, a profound neurobiological experience that may help the brain heal itself.

The key question is no longer whether psilocybin works, but how best to deliver it safely and effectively to the millions who could benefit.

Disclaimer: This article is for educational and informational purposes only. Psilocybin remains a controlled substance in most jurisdictions. Always consult qualified healthcare professionals regarding any treatment decisions.