How does psilocybin work in the brain?

It may be helpful to watch these videos to understand the theories of how psilocybin mushrooms came to be used in ancient cultures and summaries of how it works inside the brain.  It’s not important that you totally understand this material, but it does help you understand what happens in your brain when you take either a micro-dose or a regular dose.  I think this will help you trust the medicine.

In this first video, discover the transformative potential of mushrooms and psychedelics in expanding human consciousness and unlocking deeper spiritual awareness. This video explores how psilocybin mushrooms interact with the brain to enhance cognitive function, alter perception, and promote mental health breakthroughs. Learn about the connection between psychedelic experiences, consciousness exploration, and the future of mind expansion and therapy.

https://www.youtube.com/watch?v=ygoAXqpHE6Q

The following video breaks down how low doses and regular doses of psilocybin affect the brain in completely different ways, from subtle mood shifts over weeks to dramatic changes in neural connectivity within hours. They explore the science behind neuroplasticity, the default mode network, emotional regulation, and why some people feel calmer while others experience profound perspective shifts. Using current research in neuroscience, this is a grounded look at how psilocybin reshapes the brain and mind.

https://www.youtube.com/watch?v=J2f8BNLKfp4

The next video breaks down the neuroscience behind magic mushrooms, from changes in neural connectivity to how the default mode network quietens down. You’ll learn how psilocybin increases neuroplasticity, alters perception, and helps the brain break out of rigid thought loops linked to depression and anxiety. Using clear explanations, this is a grounded look at how psilocybin “changes your mind.”

https://www.youtube.com/watch?v=wYimtJBIuGE

In the following video, explore the profound effects of psilocybin on the brain and its potential to unlock higher states of awareness, neuroplasticity, and cognitive flexibility. This video delves into the science behind psilocybin's impact on brain networks, including the default mode network, and how it promotes emotional healing, mindfulness, and enhanced perception. The therapeutic benefits of psilocybin for mental health conditions such as depression and anxiety, is becoming clear to medical and behavioral health professionals.

https://www.youtube.com/watch?v=JFnPTDla4Cc

In a 2014 study, researchers (Petri, et al) looked at brain networks in a different way. Instead of focusing only on individual points and connections, they looked at patterns that appear in the network as a whole. To do this, they studied special shapes in the network called homological cycles. These shapes show loops and patterns that form when many connections work together. Using these patterns, they created something called homological scaffolds. These are tools that help summarize the important shapes in the brain network. They make it easier for scientists to study and understand how the brain’s connections are organized.

When they applied this method to 15 healthy volunteers who received either a placebo or psilocybin, they found a striking difference. After psilocybin, the brain’s functional networks became much more dynamic and flexible. Many short-lived connection patterns appeared and disappeared, along with a few strong, lasting patterns that were not seen with the placebo. This suggests that psilocybin temporarily reorganizes how different parts of the brain communicate, creating a more fluid and less rigid pattern of brain activity than normal waking consciousness.

Petri G, et al. (2014). Homological scaffolds of brain functional networks. J R Soc Interface. Dec 6;11(101):20140873. https://pmc.ncbi.nlm.nih.gov/articles/PMC4223908/

The next video is based on the recent study by Joshua Siegal and his team at Washington University in St. Louis:  Siegel JS, et al. (2024) Psilocybin desynchronizes the human brain. Nature. Aug;632(8023):131-138. doi: 10.1038/s41586-024-07624-5. https://pmc.ncbi.nlm.nih.gov/articles/PMC11291293/

It was produced by the North Spore company.  There is a short commercial in the middle of the video:

https://www.youtube.com/watch?v=Pyo6Uyhogm8

The following video with Chase Hughes gets a little more detailed as he explains research that shows how psilocybin causes the Default Mode Network to quieten down while it causes other areas of the brain become more activated. It has to do with the differences in the brain cell types between the DMN and the other parts of the brain.  I became very curious how this could be true and found the information below that explains it and is discussed in the article that this video summarizes…but watch the video first.

Chase Hughes is a leading expert in behavioral profiling, interrogation, and influence, known for his work with military, intelligence, and law enforcement. He's recognized as a top CEO and an influential figure in understanding real human patterns, not just superficial actions, having worked on advanced tactics for critical intelligence operations.

https://www.youtube.com/watch?v=lZ3_GUilpnk

Why is there a difference between how the DMN reacts to psilocybin and how other parts of the brain react to psilocybin? 

Studies show that psilocybin alters the connectivity of brain cells in a manner that is highly specific to the specific brain networks. This info is quite detailed, but it seems to answer my questions.

·      After you take psilocybin, the pyramidal tract (PT) subtype of neurons begins to respond more than the intratelencephalic (IT) subtype of neurons.  The PT neurons send commands to the body – mainly to the areas involved with the senses and movement.  PT neurons send less commands to areas involved in self-control, overthinking and rumination – i.e. the Default Mode Network.

·      In contrast, the intratelencephalic (IT) subtype of neurons that helps brain areas connect and communicate with each other. The IT neurons react in the opposite way of the PT neurons.  They begin forming new connections with different parts of the brain and seem to bypass the Default Mode Network as they make new connections.

·      These changes appear to persist in studies in rodents. This is the ‘window of opportunity’ of 21 days to strengthen new patterns that are positive and therapeutic when coping with depression, anxiety and stress. These studies have not been done in humans but the brain in rodents is similar enough to the human brain to interpret the results to humans.

The other big “take-away” from this study is that they found that when the connections in the DMN are weakened, that the study participant ‘can become what they focus on.’  One’s sense of Self is not fixed. One can rewrite the script of who they are when the new connections are made in the other parts of the brain.  Chase Hughes states that this possibly be dangerous – perhaps to brainwash the enemy – but that seems unlikely.  Just remember when Chase says, “They control you” that “they” is really YOU and your inner healing intelligence.  You decide what your intention is.  You decide what to focus your attention on during and after your journey.  You can choose who you want to become as you do your Integration.

Jiang, Quan et al (2026). Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks Cell, Volume 189, Issue 2, 659 - 675.e22

https://news.cornell.edu/stories/2025/12/dose-psilocybin-dash-rabies-point-treatment-depression

The cartoon below shows why these differences happen…just in case you’re interested…if not, that’s OK! 

·      We have PT and IT cells everywhere in the pre-frontal cortex.

·      There are different ratios of PT and IT cells in different part of the brain.

·      The DMN is illustrated as the ‘maestro’ and when it is active, it controls the senses, emotions and the body.  The PT cells in the DMN aren’t more numerous in the DMN but they influence it more than the IT cells.

·      After taking psilocybin, the DMN is less activated, and the IT cells begin to proliferate in the other parts of the brain. IT cells specialize in linking brain areas, creating new associations and making the brain networks more flexible.

·      The connections between networks that normally don’t communicate begin communicating.  This leads to dendrite connection, growth, increased openness and dialogue.

During the 3 week period of time that psilocybin has altered connections in your brain is the time when dendrites are beginning to grow longer and denser as this picture shows:

Psilocybin Pathways in the Brain

After you consume psilocybin mushrooms, your body metabolizes it into a compound called psilocin. If you compare the chemical structure of psilocybin to serotoninin (5HT), you can understand how psilocin attaches to serotonin receptors in the body. There are many different serotonin receptors in the body and psilocin binds to each of them with different affinities. You can see that the main serotonin receptor that leads to the “psychedelic effect” in the brain is 5HT2A. Psilocin binds to the others listed in the diagram below - having the lowest affinity for 5HT1B and an increasing affinity for binding as you look up the list.

The Ds in this list refers to dopamine - we are not going to dive into that topic.

The first pathway on the left side is via the 5HT2A - a serotonin receptor. When the dose of psilocin is approximately 7 mg, this is when the psychedelic effects occur. If you take a micro-dose of about 2mg of psilocin, this pathway is not activated enough to cause any psychedelic effects. However, the reactions in the middle and on the right occur to a lesser degree. This is because the first pathway catalyzes the second and third pathways - shown by the horizontal arrows.

The middle part of the diagram shows the second pathway, which results in the activation of the AMPA and NMDA receptors. These brain receptors work together to help the brain learn and form memories. They are both activated by the neurotransmitter, glutamate, which is the main excitatory (activating) chemical signal in the brain. AMPA receptors allow neurons to talk to each other quickly. NMDA receptors help the brain recognize “this connection is important—strengthen it.”‍ ‍They work together to produce a process called Long‑Term Potentiation, which is one of the main biological mechanisms behind learning and memory.

The right side of the diagram shows the third metabolic pathway that stimulates dendrite growth via the Brain Derived Neurotropic Factor (BDNF) pathway.   The BDNF pathway is one of the brain’s most important systems for learning, memory, and neuroplasticity. This is the brain’s ability to change and rewire itself. BDNF binds to a receptor on neurons called the TrkB receptor. Activation of the TrkB receptor triggers several important molecular pathways, including:

• MAPK/ERK signaling pathway – helps control gene expression related to learning

• PI3K-Akt signaling pathway – promotes neuron survival and growth

• PLCγ signaling pathway – helps strengthen synapses

This leads to Ca2+ influx and initiation of signaling cascades that promote dendritic spine enlargement or the formation of new spines. When calcium (Ca²⁺) signals stay active in a neuron for a while, they trigger important changes in the cell. One of the first things that happens is that a protein called CREB becomes activated. CREB then moves into the cell’s nucleus, where the DNA is located.

Once in the nucleus, CREB turns on a group of very fast-acting genes called immediate early genes (IEGs), such as c-fos and jun. These genes act like “master switches” that activate many other genes involved in transcription of DNA.

Those downstream genes produce plasticity-related proteins (PRPs)—proteins that help the brain change and adapt. These include:

• new receptors that help neurons communicate;

• structural proteins that strengthen or reshape synapses;

• neurotrophins, which support neuron growth and survival.

Through its receptor TrkB, BDNF activates multiple signaling pathways, including Akt and ERK, to sustain plasticity and promote its own expression in a positive feedback loop. In parallel, mTORC1 is activated both downstream of BDNF and through Ca2+-sensitive mechanisms, supporting local translation of synaptic proteins essential for structural remodeling.

This process also helps produce Long-Term Potentiation, a key biological mechanism of memory. The BDNF pathway converts neural activity and experience into physical changes in brain connections, allowing learning, emotional healing, and memory formation.

Ketamine works primarily by only blocking the NMDA receptor, which also causes a surge of glutamate signaling and activation of BDNF pathways. Current evidence suggests psilocybin-induced structural changes may persist longer, while ketamine produces a faster but often shorter-lived plasticity window.

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147%2825%2900200-7#f0005

Several serotonin receptors in the brain; especially 5‑HT1 receptor, 5‑HT2 receptor, 5‑HT3A receptor, and 5‑HT7 receptors help regulate how the body processes pain. However, their effects vary depending on factors such as where the receptors are located, the dose of drugs affecting them, how the drug is administered, and the type and duration of pain.

Among the other serotonin receptors, 5‑HT2C receptor appears to play an important role in the psychedelic effect of psilocybin. When the serotonin blocker ketanserin is given before psilocybin, it prevents this receptor from contributing to the psychedelic effects.

Activation the 5‑HT2A receptor, may also reduce inflammation. When this receptor is stimulated, it can suppress several inflammatory signaling pathways, including Tumor Necrosis Factor‑alpha, a key molecule involved in inflammation, infection, cancer, and neuropathic pain. Because TNF-related inflammation in the nervous system may contribute to chronic pain, reducing TNF signaling could potentially have therapeutic benefits.

This anti-inflammatory effect may also influence other immune molecules such as ICAM-1, VCAM-1, IL-5, and GM-CSF, which are involved in immune responses and inflammatory diseases. Because of this, serotonin-related signaling pathways might have therapeutic potential in conditions such as eosinophilic asthma.

Importantly, the anti-inflammatory effects of psilocybin may not require doses high enough to produce a full mystical psychedelic experience, although this has not yet been fully studied.

Dodd S, et al. (2023). Psilocybin in neuropsychiatry:  a review of its pharmacology, safety, and efficacy.  CNS Spectrums 28(4):416.

Cortes-Altamirano JL, et al.  (2018).  Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 Receptors and their Role in the Modulation of Pain Response in the Central Nervous System. Curr Neuropharmacol 16(2):210-221.

Flanagan TW & Nichols CD. (2018): Psychedelics as anti-inflammatory agents. International Review of Psychiatry DOI: 10.1080/09540261.2018.1481827.

Aldhalmi AK, et al. (2022).  Association of Tumor Necrosis Factor-α and Myeloperoxidase enzyme with Severe Asthma: A comparative study. Rep Biochem Mol Biol 11(2):238-245.

Yu B, et al.  (2008).  Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. J Pharmacol Exp Ther 327(2):316-23.

More detailed information can be found at: https://www.cambridge.org/core/journals/cns-spectrums/article/psilocybin-in-neuropsychiatry-a-review-of-its-pharmacology-safety-and-efficacy/AA1FB4F49C14BA3F398238D6E5A3947A