Psilocybin and the brain: what happens at the neuron and network level?

Psilocybin is best known for its mind-altering effects, think visual patterns, altered time perception and profound insights. Therefore, a lot happens in the brain during a psilocybin experience through truffles and magic mushrooms, for example. This is less visible, but still very interesting scientifically. In this article, therefore, we look at how psilocybin acts at both the neuronal level and at the level of large-scale brain networks. ¹

Psilocybin changes the brain not by causing damage, but by temporarily reorganizing the way brain networks communicate with each other. As a result, neural flexibility increases and fixed patterns of thought and perception briefly fall away.

Psilocybin is a prodrug found in certain mushrooms and truffles. The body quickly converts it into psilocin, a substance that is actually active in the brain. It is chemically very similar to serotonin (5-HT). This neurotransmitter plays a central role in mood, perception and cognitive flexibility. This structural similarity allows psilocin to bind to serotonin receptors, particularly the 5-HT2A receptor, which is abundant in the cortex.²

Psilocybin is unique because it:

• Temporary and reversible brain organization changes
• Deep changes in subjective experience caused
• Provides insight into how consciousness arises from brain activity
• Therapeutic potential shows in depression, anxiety and addiction

Psilocybin often functions for neuroscientists as a kind of “disruption tool.” It allows controlled intervention in brain networks, revealing how normal functioning is organized in the brain.

1. Attenuation of the Default Mode Network (DMN).

Among other things, studies regularly find decreases in activity and coherence in the Default Mode Network. This network is involved in self-reflection, ego-thinking and brooding, among other things. Reduced DMN activity correlates strongly with experiences such as ego dissolution and a reduced sense of a separated “me.”

2. Increased communication between networks.

Connectivity between normally separate brain networks increases simultaneously. Sensory, emotional and cognitive areas generally communicate more freely with each other through psilocybin. This explains, among other things, synesthesia-like experiences, more intense emotions and new associations and insights. Thus, psilocybin temporarily switches the brain from a segmented to a more integrated network model.

3. Decrease in hierarchical control.

Normally, higher brain regions control lower sensory areas. This top-down control is weakened by psilocybin. This gives bottom-up information more influence, think sensory and emotional responses. This contributes to the intensity of perception.

Activation of 5-HT2A receptors.

Psilocin binds primarily to 5-HT2A receptors on pyramidal neurons in the cortex. These receptors are primarily located in higher association regions, including the prefrontal cortex and parietal regions. Activation of these receptors leads to increased neuronal excitation, increased synaptic “noise” and altered glutamate release. In other words, neurons fire less predictably and less hierarchically. ²

Increase in neural flexibility

The entropy of brain signals increases under psilocybin. This means that brain activity follows less rigid patterns and explores more possible states. Scientists often described this as a more flexible and less jammed brain. Moreover, this mechanical is associated with therapeutic effects in depression, as brain networks tend to function too rigidly just then. ¹

1. Transience of effects: The network changes caused by psilocybin are temporary. They usually return to baseline within 6 to 8 hours.
2. Individual differences: The degree of DMN attenuation and network integration varies from person to person and is related to personality, expectation and setting.
3. Dose dependence: The dose has a lot of influence on the effects. Lower doses tend to cause subtle network changes, while higher doses result in stronger disintegration and reorganization of the brain.

Want to learn more about psilocybin and its various natural sources? Psilocybin is found, among other things, in magic mushrooms and magic truffles. Although the active ingredient is the same, the form, strength and experience of use may differ. More background information about these differences can help to better understand the effects on the brain and consciousness.

1. PNAS – Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin (2012)
2. Journal of Neuroscience – Broadband Cortical Desynchronization Underlies the Human Psychedelic State (2013)
3. PNAS – Effective connectivity changes in LSD-induced altered states of consciousness in humans (2019)

This article is intended for educational purposes and does not replace medical or psychological advice. Psilocybin is regulated or banned in many countries. Use may carry risks, especially in psychologically vulnerable people.