Psilocybin and the brain
When psilocybin from truffles or mushrooms is converted into psilocin in the body, a remarkable journey through the brain begins. This active molecule binds primarily to the 5-HT₂A receptors, which are present in high concentrations in various brain regions. The result is a chain of changes in perception, emotion, and consciousness, which together explain the intensity and depth of a psychedelic experience. To understand why a psilocybin session can have such a powerful effect, it's valuable to examine how psilocin exerts its influence on each brain region. In this blog post, we'll take you step by step through the brain's most important pathways. We'll go from the neocortex to the amygdala and from the hippocampus to the vagus nerve. Discover how their interaction makes the unique experience of a truffle journey possible.
Neocortex
Normal role
The neocortex, especially the associative areas in the frontal and parietal cortex, is where abstract thought, self-awareness, planning, and meaning-making take place. Within the default mode network (DMN) The medial prefrontal cortex and the posterior cingulate cortex form hubs that govern your self-image, reflection, and internal dialogue. This network dominates at rest, while it is suppressed during external tasks.
Receptor density
The neocortex contains the highest concentration of 5-HT₂A receptors, particularly in layers III and V of the pyramidal cells. These cells are crucial for long-distance communication between brain regions. It is precisely this distribution that explains why psychedelics have such a powerful effect on perception and cognition.
Effect of psilocin
When psilocin binds to the 5-HT₂A receptors, it increases the excitability of the pyramidal cells. The result is a desynchronization of brain rhythmsAlpha and beta waves (which normally bring stability and predictability to your cognition) decrease, creating a state in which networks function less rigidly. The DMN loses its dominant control, causing "rigid priors" (fixed assumptions and thought patterns) to loosen. Subjectively, this can feel like "ego dissolution"—a sense of blurring the boundaries between yourself and the world.
Side effects
Because the neocortex loses its tight grip, other brain areas gain greater influence. Sensory input is perceived more strongly, emotions from the limbic system are felt more intensely, and old memories are more easily reintegrated. Post-acutely, this temporary flexibility is transformed into structural plasticity: studies show that dendritic spines in the frontal cortex remain larger and more numerous for weeks after psilocybin, suggesting lasting changes in connectivity and learning ability.
Anterior Cingulate Gyrus
Normal role
The anterior cingulate gyrus (ACC) is a crucial link between emotion and cognition. It monitors errors and conflicts, shifts attention to relevant stimuli, and regulates pain and emotional charge. The ACC is part of the salience network, which decides which stimuli are important enough to focus your attention on.
Receptor density
The ACC is one of the cortex areas with a lot of 5-HT₂A receptors, which makes it susceptible to psychedelic influences.
Effect of psilocin
Under the influence of psilocin, the ACC becomes less strict in its transmission of salience information. This means that not only threats or important external tasks are prioritized, but also subtle, often ignored signals (interoceptive, emotional, or spiritual) can enter consciousness. This can lead to a feeling of experiencing emotions more "honestly" or intensely. Simultaneously, flexibility in cognitive control increases, which is why people often find themselves more open to new perspectives during a session.
Side effects
Because the ACC influences both the amygdala (fear/emotion) and the prefrontal cortex (logical thinking), psilocin can integrate emotions and cognition in a new way. This explains why people often emerge from a session with greater self-compassion or empathy: the rational and emotional are no longer seen as opposing forces, but as complementary sources of wisdom.
Caudate nucleus
Normal role
The caudate nucleus is part of the striatum and is strongly involved in habitual behavior, decision-making, and loops of recurring thoughts. In collaboration with the thalamus and cortex, it forms cortico-striatal-thalamo-cortical (CSTC) loops that maintain both motor and cognitive habits.
Receptor density
There are fewer 5-HT₂A receptors present here than in the cortex, but there are still relevant quantities 5-HT₂C and dopaminergic modulation which are influenced indirectly via serotonergic systems.
Effect of psilocin
Psychedelics "loosen" the CSTC loops. This means that fixed patterns – such as worrying or obsessive thought patterns – are temporarily interrupted. Functional research with LSD (very similar to psilocin) shows that the feedback dynamics between thalamus, striatum and cortex changes, which is subjectively experienced as space or flexibility in thinking and doing.
Side effects
This relaxation allows new behavioral strategies or insights to emerge. This explains why psychedelics have therapeutic potential for obsessive-compulsive disorders and addiction: the system that rigidly repeats normal behavior and thoughts temporarily becomes less dominant, allowing you to explore new paths.
Hypothalamus
Normal role
Through input from the cortex and limbic structures (particularly the amygdala and hippocampus), psilocin indirectly affects the hypothalamus. This can cause bodily sensations to change during a session: you might feel warmer or colder, less or more thirsty, or notice a shift in sexual energy.
Receptor density
The hypothalamus has serotonergic innervation, including. 5-HT₁A and 5-HT₂A-receptors, although the density is lower than in the cortex.
Effect of psilocin
Through input from the cortex and limbic structures (particularly the amygdala and hippocampus), psilocin indirectly affects the hypothalamus. This can cause bodily sensations to change during a session: you might feel warmer or colder, less or more thirsty, or notice a shift in sexual energy.
Side effects
Because the hypothalamus influences hormonal systems, psilocin can also stress axis (HPA axis) Modulate. This can lead to feelings of relaxation and connection, as cortisol responses are dampened and oxytocin/serotonin systems are more active. This explains the profound physical calm and security that many users experience.
Amygdala
Normal role
The amygdala is the emotional center of the brain and plays a crucial role in perceiving threats, regulating fear responses, and linking emotions to memories. Through this function, the amygdala largely determines how intensely we experience events and how emotional experiences are stored in our memory.
Receptor density
The amygdala has both 5-HT₁A as 5-HT₂A-receptors, which modulate its reactivity.
Effect of psilocin
During the acute trip, amygdala activity often decreases, especially in response to emotionally negative stimuli. In healthy participants, this leads to a more positive mood. In patients with depression, it has been observed that the amygdala activity decreases in the days following the session. more emotionally responsive becomes. This is not in the sense of fear, but in the sense of openness to allow emotions.
Side effects
This two-phase effect makes therapy more powerful: during the session, anxiety is reduced, allowing you to explore difficult topics. After the session, emotional responsiveness is restored, so that new insights are not suppressed but rather experienced.
Hippocampus
Normal role
The hippocampus is the brain's memory center, responsible for recording new memories and placing them in context. It also gives meaning to events by linking them to emotions, working closely with the amygdala. At the same time, the hippocampus maintains close contact with the cortex, where memories are ultimately stored long-term. In this way, the hippocampus forms a link between present-day experience and the enduring narratives that shape our self-image and life history.
Receptor density
The hippocampus is rich in 5-HT₁A receptors and also contains 5-HT₂A, albeit in lower concentrations than the cortex.
Effect of psilocin
Under the influence of psilocin, memories can be recalled and placed in a new emotional framework. This is associated with rapid neuroplastic changes: dendritic spine growth, increased BDNF expression and activation of the mTOR/TrkB pathway.
Side effects
The result is that old memories don't disappear, but their meaning can change. Traumas can be relived with more gentleness, allowing the brain to create a new narrative around the same events—a crucial step in psychotherapeutic recovery.
Thalamus
Normal role
The thalamus functions as a central relay station in the brain, determining which stimuli from the senses are passed on to the cortex. It filters sound, images, touch, and internal signals, ensuring that only the most relevant information reaches our consciousness. In this way, the thalamus plays a key role in attention and perception: it regulates whether we ignore a faint background noise or suddenly look up at an unexpected sound. As a gatekeeper between the external world and conscious thought, the thalamus largely determines how we experience reality.
Receptor density
The thalamus has serotonergic receptors, but fewer than the cortex. Nevertheless, its central position means it plays a significant role in psilocin's effects.
Effect of psilocin
Psilocin disrupts thalamic filtering, allowing more and more intense stimuli to reach the cortex. This explains why sound, color, and touch are experienced more intensely. It can also cause hallucinations, as irrelevant or internal signals become conscious unfiltered.
Side effects
The thalamus's increased permeability amplifies the sensory richness of a trip and contributes to synesthesia (when the senses blend). This abundance of input feeds the neocortex, which attempts to integrate it meaningfully.
Corpus callosum
Normal role
The corpus callosum is a thick bundle of nerve fibers that connects the left and right hemispheres of the brain. This structure allows the two hemispheres to continuously exchange information and complement each other's functions. The left hemisphere, often more involved in language and analytical thinking, is thus coordinated with the right hemisphere, which specializes more in creativity, intuition, and holistic perception. The corpus callosum thus ensures that reason and emotion, logic and imagination, do not function separately but are interwoven into a seamless whole.
Receptor density
Although the fibers themselves do not contain receptors, the connected cortex areas are rich in 5-HT₂A.
Effect of psilocin
Under psilocin, interhemispheric communication increases. People experience this as a merging of reason and emotion, or as images directly connected to language and meaning.
Side effects
This increased integration creates creative insights that make both logical and emotional sense – a rare synergy often experienced as a “revelation.”.
Cerebellum
Normal role
The cerebellum, also known as the little brain, is traditionally known as the center that precisely coordinates movement and timing. It ensures the fluidity and precision of our actions, from walking and writing to playing music. Besides this motor role, the cerebellum also appears to be involved in emotional regulation and cognitive prediction: it helps predict what will happen next and thus contributes to smooth responses to the environment. This makes the cerebellum not just a motor organ but a sophisticated regulator that balances body, emotion, and thought.
Receptor density
Serotonergic receptors are present, but the density is lower than in the associative cortex.
Effect of psilocin
The cerebellum shows that movements can be experienced more fluidly and breathing more consciously. The subjective experience of time also changes because the internal clock is influenced.
Side effects
By connecting with sensory and frontal networks, the cerebellum enhances bodily harmony during a trip. This makes dance, breathing, or meditation feel extra connected and meaningful.
Brainstem and raphe
Normal role
The raphe nuclei in the brainstem are the brain's primary source of serotonin. From these nuclei, widespread serotonergic projections are sent to virtually all brain areas, playing a central role in mood, sleep, pain perception, and emotional regulation. The brainstem itself also regulates fundamental bodily functions such as breathing, heart rate, and alertness or arousal. Together, the raphe nuclei and surrounding structures ensure that our brain can function in a stable physiological and emotional state, serving as a foundation upon which higher cognitive and emotional processes build.
Receptor density
The raphe contains 5-HT₁A autoreceptors, which regulate their own rate of fire.
Effect of psilocin
Psilocin activates these autoreceptors, temporarily reducing natural serotonin release. Simultaneously, it activates 5-HT₂A receptors elsewhere, leading to a brain-wide change in signal transmission.
Side effects
This explains why psilocin isn't simply a "serotonin boost," but a complete reconfiguration of serotonergic balance. Through connections with the nucleus tractus solitarius, it also affects the autonomic nervous system, resulting in altered heart rate, breathing, and feelings of relaxation or surrender.
Vagus nerve
Normal role
The vagus nerve is the tenth cranial nerve and forms a vital connection between the brain and the body. It sends signals from organs such as the heart, lungs, and intestines to the brain and vice versa. The ventral branch normally promotes social connection, calm, and safety. The dorsal branch, on the other hand, plays a role in immobilization and energy conservation, for example, during extreme stress or deep relaxation.
Receptor density
The vagus nerve itself contains few serotonergic receptors. However, this nerve has strong connections to brain areas rich in 5-HT₂A receptors, such as the insula, the anterior cingulate cortex, and the prefrontal cortex. These brain areas can indirectly influence vagal activity. This explains why serotonergic substances like psilocin have a noticeable effect on the autonomic functions controlled by the vagus nerve.
Effect of psilocin
Psilocin primarily activates 5-HT₂A receptors, altering communication patterns in brain areas related to the vagus nerve. This increases the ventral vagus nerve's activity, leading to feelings of warmth, love, connection, and safety. At higher doses, the balance can shift, and the dorsal vagus nerve becomes more involved, potentially leading to a state of surrender and immobility. Many people experience this as a form of "ego death," in which the boundaries of the self temporarily collapse.
Side effects
The first step is increased serotonergic activity in brain areas that regulate the vagus nerve. This translates into increased ventral vagal activity and a physiological state of safety. From there, a cascade of effects follows: relaxation of heart rate and breathing, a greater sense of connection with others, and a deep physical sense of calm. At higher doses, a shift toward dorsal vagal dominance occurs, which can manifest as a physical surrender or trance-like state. This combination of phases explains why psilocin can evoke both loving connection and transcendent letting go.
Conclusion
The journey psilocin triggers in the brain isn't limited to a single region but rather arises from the collaboration of many areas. By loosening the neocortex's fixed patterns, reducing the amygdala's fearful responses, allowing the hippocampus to reframe old memories, and strengthening the vagus nerve's sense of connection, a unique state of consciousness emerges. This temporary reconfiguration of the brain opens the door to greater flexibility in thinking and feeling, and can lead to profound insights, emotional processing, and lasting neuroplastic changes. This explains why psilocybin not only evokes a remarkable experience but also holds such great therapeutic potential for personal growth and recovery.
Those interested in learning more about how these changes are subjectively experienced can read more in our article about the truffle journey. For a more in-depth look at the effects of psilocybin and psilocin at the cellular level, we refer you to the article "Psychotherapy with psychedelic therapy is often not necessary." This will provide insight into both the inner experience and the biological basis of these unique substances.
Experience it yourself under supervision
At Triptherapie, you can experience the effects of psilocybin and psilocin in a safe and meaningful way under the guidance of an experienced therapist or trip sitter. There are two steps to make an appointment. The first is completing the intake form, so we can thoroughly assess your health, intentions, and wishes. The second step is choosing and booking the session that best suits you, after which we will further develop the process together.