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

The other big “take-away” from this s 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 to me.  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 and rewrite your story as you do your Integration. This is how some people have one medium to large dose and it changes their mind.

Below is the infographic from 2026 study that Chase Hughes is referring to in his video.

Jiang Q, et al. (2026). Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks Cell, Volume 189, Issue 2, 659 - 675.e22. https://www.cell.com/cell/fulltext/S0092-8674(25)01305-4

• Psilocybin strengthens pathways that route sensory inputs to subcortical regions - the PT neurons that go to the brainstem, and downward through the body via the spinal cord and ipsilateral striatum

• Psilocybin weakens inputs associated with cortico-cortical feedback loops - the IT neurons in the Default Mode Network

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

During the 2 -3 weeks 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 D1 and D3 in this list refers to dopamine and you probably know that dopamine makes your feel calmer and happier. There’s more about dopamine later on.

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.

More about dopamine

We know that psilocybin attaches to serotonin receptors called 5-HT2A receptors on pyramidal neurons, which are major communication cells in the cortex. Psilocybin also activates and then regulates the amount of dopamine released.

• Striatal Dopamine Release: Human positron emission tomography (PET) scans show that psilocybin significantly increases endogenous dopamine concentrations in the striatum. This displacement of receptor-bound tracking agents indicates that a wave of dopamine is physically flooding the environment where D1 and D3 reside.

• Hyper-Activation of D1: The elevated dopamine levels in the prefrontal cortex and striatum intensely stimulate D1 receptors. In the science of learning and behavioral reinforcement, the high D1 activation drives the “direct pathway” which promotes neuroplasticity, novelty-seeking behavior, and shifts in perception.

• Regulatory Pull of D3: Because D3 receptors have a fundamentally high affinity for dopamine, they are incredibly sensitive to the massive influx of dopamine triggered by psilocybin. D3 receptors in the limbic system and ventral striatum engage as a regulatory brake, managing the intense emotional processing, euphoria, and depersonalization associated with the psychedelic experience.

• Sensitization Effects: Studies on psychedelic mechanisms suggest that initial serotonin

• activation serves to sensitize downstream dopamine pathways. This cross-talk fundamentally alters receptor sensitivity, allowing even minor amounts of subsequent dopamine to provoke a more pronounced cellular response.

When these receptors are activated, the pyramidal neurons release more glutamate, the brain’s main “go” signal. Glutamate helps different parts of the brain communicate and stimulates the growth of new connections between neurons. This increased communication also may help people break out of rigid patterns of thinking, such as rumination, hopelessness, and negative self-talk that are common in depression. This is where ketamine exerts it main mechanism of action for depression.

The burst of glutamate also activates GABA-producing interneurons. GABA is the brain’s main “calming” signal. These interneurons act like brakes, helping quiet circuits that are overactive during stress, anxiety, and depression. As these circuits become less noisy and more balanced, people may feel calmer, less emotionally overwhelmed, more able to think clearly and hopefully less depressed.

Together, the temporary increase in glutamate and the balancing effect of GABA may improve mood by making the brain more flexible and less stuck in unhealthy patterns. At the same time, glutamate promotes neuroplasticity—the brain’s ability to form and strengthen new connections—which may help support lasting positive changes in mood, perspective, and behavior.

References for this material:

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.

Casanova, A, et al. (2024). The influence of psilocybin on subconscious and conscious emotional learning. iScience 27(6): 110034. https://doi.org/10.1016/j.isci.2024.110034.

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.

Szpręgiel I, Bysiek A. Psilocybin and the glutamatergic pathway: implications for the treatment of neuropsychiatric diseases. Pharmacol Rep. 2024 Dec;76(6):1297-1304.

Vollenweider, F., Vontobel, P., Hell, D. et al. 5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride. Neuropsychopharmacol 20, 424–433 (1999). https://doi.org/10.1016/S0893-133X(98)00108-0

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