Psilocybin and the brain
When psilocybin from truffles or mushrooms is converted into psilocin in the body, a special journey through the brain starts. This active molecule attaches mainly to the 5-HT₂A receptors, which are present in high concentration 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 is valuable to look at how psilocin exerts its influence per brain region. In this blog, we will take you step by step through the most important links in the brain. We go from the neocortex to the amygdala and from the hippocampus to the vagus nerve. Find out how their cooperation makes the unique experience of a truffle trip possible.
Neocortex
Normal role
The neocortex, especially the associative parts in the frontal and parietal cortex, is where abstract thinking, self-awareness, planning and meaning-making take place. Within the default mode network (DMN) the medial prefrontal cortex and the posterior cingulate cortex form nodes that direct your self-image, reflection and inner dialogue. At rest, this network dominates, while it is suppressed during external tasks.
Receptor density
The neocortex contains the highest concentration of 5-HT₂A receptors, especially 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 pyramidal cells. The result is a desynchronisation of brain rhythms: alpha and beta waves (which normally bring stability and predictability to your cognition) diminish, and a state emerges in which networks function in a less tightly bounded way. 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 that boundaries between oneself and the world are blurring.
Side effects
As the neocortex loses its tight grip, other brain regions gain more influence. Sensory input comes through more strongly, emotions from the limbic system feel more intense, and old memories are more easily reintegrated. Post-acute, you can see that this temporary flexibility is transformed into structural plasticity: studies show that dendritic spines in the frontal cortex are larger and more numerous for weeks after psilocybin, indicating lasting changes in connectivity and learnability.
Anterior Cingulate Gyrus
Normal role
The anterior cingulate gyrus (ACC) is a crucial link between emotion and cognition. It monitors errors and conflicts, switches 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 belongs to the cortex regions with many 5-HT₂A receptors, making it susceptible to psychedelic influence.
Effect of psilocin
Under the influence of psilocin, the ACC becomes less strict in relaying salience information. This means that not only threats or important external tasks are prioritised, 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. At the same time, flexibility in cognitive control increases, so people often experience being more open to new perspectives during a session.
Side effects
Because the ACC has its influence on 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 come out of a session with more 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 behaviour, decision-making and loops of recurring thoughts. In cooperation with the thalamus and cortex, it forms cortico-striatal-thalamo-cortical (CSTC) loops that maintain both motor and cognitive habits.
Receptor density
Fewer 5-HT₂A receptors are present here than in the cortex, but relevant amounts 5-HT₂C and dopaminergic modulation affected indirectly via serotonergic systems.
Effect of psilocin
Psychedelics "loosen" the CSTC loops. This means that fixed patterns - for example, brooding or obsessive thought loops - 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 perceived as space or flexibility in thought and action.
Side effects
This loosening allows new behavioural strategies or insights to penetrate. This explains why psychedelics have therapeutic potential in compulsive disorders and addiction: the system that rigidly repeats normal behaviour and thoughts becomes temporarily less dominant, allowing you to explore new paths.
Hypothalamus
Normal role
Via input from cortex and limbic structures (especially the amygdala and hippocampus), psilocin affects the hypothalamus indirectly. As a result, bodily sensations may change during a session: you may 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
ia input from cortex and limbic structures (especially the amygdala and hippocampus), psilocin affects the hypothalamus indirectly. As a result, bodily sensations may change during a session: you may feel warmer or colder, less or more thirsty, or notice a shift in sexual energy.
Side effects
Because the hypothalamus affects hormonal systems, psilocin can also affect the stress axis (HPA axis) modulate. This can lead to feelings of relaxation and connectedness, as cortisol responses dampen and oxytocin/serotonin systems become more active. This explains the deep physical calm and security experienced by many users.
Amygdala
Normal role
The amygdala forms the emotional centre of the brain and plays a crucial role in perceiving threat, regulating fear responses and linking emotions to memories. Through this function, the amygdala strongly 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
ithin the acute trip, amygdala activity often decreases, especially in the presence of emotionally negative stimuli. In healthy participants, this leads to a more positive mood. In patients with depression, it has been observed that in the days following the session, the amygdala actually 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-stage effect makes therapy more powerful: during the session, fear is muted, daring you to touch difficult themes. After the session, emotional responsiveness is restored, so new insights are not pushed away but rather lived through.
Hippocampus
Normal role
The hippocampus is the memory centre of the brain and is responsible for capturing new memories and placing them in context. In doing so, it gives meaning to events by linking them to emotions, in close cooperation with the amygdala. At the same time, the hippocampus maintains intensive contact with the cortex, where memories are ultimately stored for the long term. In this way, the hippocampus forms a link between experience in the moment and the enduring stories that determine our self-image and life history.
Receptor density
The hippocampus is rich in 5-HT₁A receptors and also contains 5-HT₂A, albeit at 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 goes along with rapid neuroplastic changes: dendritic spine growth, increased BDNF expression and activation of the mTOR/TrkB path.
Side effects
As a result, old memories do not disappear, but their charge can change. Trauma can be relived with more gentleness, allowing the brain to create a new story around the same facts - a crucial step in psychotherapeutic recovery.
Thalamus
Normal role
The thalamus acts as a central switching station in the brain, determining which stimuli from the senses are passed on to the cortex. It filters sound, images, touch and internal signals so that only the most relevant information reaches our consciousness. As such, the thalamus plays a key role in attention and perception: it regulates whether we ignore a soft background noise or instead look up suddenly at an unexpected sound. As a gatekeeper between the outside world and conscious thought, the thalamus thus largely determines how we experience reality.
Receptor density
The thalamus has serotonergic receptors, but fewer than the cortex. Nevertheless, due to its central position, it plays a huge role in the effects of psilocin.
Effect of psilocin
Psilocin disrupts thalamic filter function, allowing more and more intense stimuli to reach the cortex. This explains why sound, colour and touch are experienced more intensely. It can also cause hallucinations, as irrelevant or internal signals become unfiltered awareness.
Side effects
The increased permeability of the thalamus enhances the sensory richness of a trip and contributes to synesthesia (when senses mix). This abundance of input feeds the neocortex, which tries to integrate it meaningfully.
Corpus callosum
Normal role
The corpus callosum is a thick bundle of nerve fibres connecting the left and right hemispheres of the brain. This structure allows the hemispheres of the brain to constantly exchange information and complement each other's functions. The left hemisphere, which is often more heavily involved in language and analytical thinking, is thus coordinated with the right hemisphere, which is instead more specialised in creativity, intuition and holistic perception. The corpus callosum thus ensures that reason and feeling, logic and imagination, do not function separately from each other but are woven together into a fluid whole.
Receptor density
Although the fibres 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 fusion of reason and feeling, or images directly linked to language and meaning.
Side effects
This increased integration creates creative insights that make both logical and emotional sense - a rare synergy that is often experienced as "revelation".
Cerebellum
Normal role
The cerebellum, also known as the cerebellum, is traditionally known as the centre that precisely coordinates movement and timing. It ensures that our actions are fluid and precise, from walking and writing to making music. However, in addition to this motor role, the cerebellum also appears to be involved in emotional regulation and cognitive prediction: it helps estimate what is going to happen and thus contributes to smoothly responding to the environment. This makes the cerebellum not just a motor organ, but a sophisticated regulator that balances body, emotion and thinking.
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, as the internal clock is affected.
Side effects
By linking to sensory and frontal networks, the cerebellum enhances bodily harmony during a trip. Dance, breathing or meditation feel extra connected and meaningful as a result.
Brainstem and raphe
Normal role
The raphe nuclei in the brain stem are the main source of serotonin in the brain. From these nuclei, widespread serotonergic projections are sent to almost all brain regions, playing a central role in mood, sleep, pain perception and emotional regulation. In addition, the brain stem itself regulates basic bodily functions such as breathing, heart rate and level of wakefulness or arousal. Together, the raphe nuclei and surrounding structures allow our brain to function in a stable physiological and emotional state, as a foundation on 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 lowering natural serotonin release. At the same time, it activates 5-HT₂A receptors elsewhere, leading to a brain-wide change in signal transmission.
Side effects
This explains why psilocin is not simply a "serotonin boost", but a complete reconfiguration of serotonergic balance. Through connections to the nucleus tractus solitarius, it also affects the autonomic nervous system, which translates into altered heart rate, breathing and feelings of relaxation or surrender.
Vagus nerve
Normal role
The vagus nerve is the tenth cranial nerve and forms an essential connection between brain and body. It sends signals from organs such as heart, lungs and intestines to the brain and vice versa. The ventral branch normally provides social connection, peace and security. On the contrary, the dorsal branch plays a role in immobilisation and energy conservation, for example in cases of extreme stress or deep relaxation
Receptor density
There are few serotonergic receptors in the vagus nerve itself. Yet this nerve has a strong link to brain regions rich in 5-HT₂A receptors, such as the insula, anterior cingulate cortex and prefrontal cortex. Through these brain regions, vagal activity can be indirectly influenced. This explains why serotonergic substances such as psilocin have palpable effects on the autonomic functions that control the vagus nerve.
Effect of psilocin
Psilocin mainly activates the 5-HT₂A receptors, changing communication patterns in brain regions associated with the vagus nerve. This makes the ventral vagus more active, leading to feelings of warmth, love, connection and safety. At higher doses, the balance can shift and the dorsal vagus becomes more involved, leading to a state of surrender and immobilisation. Many people experience this as a form of "ego death", in which the boundaries of the self temporarily fall away.
Side effects
The first step is enhanced serotonergic activity in brain regions that regulate the vagus. This translates into increased ventral vagus activity and a physiological state of safety. From there, a cascade of effects follows: relaxation of heart rate and breathing, increased sense of connection with others and a deep physical sense of calm. At higher doses, a shift towards dorsal vagus dominance occurs, which can manifest itself in a bodily surrender or trance-like state. This combination of phases explains why psilocin can evoke both loving connection and transcendent release.
Conclusion
The journey caused by psilocin in the brain is not confined to one region but rather arises from the cooperation of many areas. By causing the neocortex to loosen its fixed patterns, the amygdala to react less anxiously, the hippocampus to place old memories in a new light and the vagus nerve to strengthen feelings of connection, a unique state of consciousness is created. This temporary reconfiguration of the brain opens the door to greater flexibility in thinking and feeling, and can lead to deep insights, emotional processing and lasting neuroplastic changes. This explains why psilocybin not only evokes an extraordinary experience, but also has such great therapeutic potential for personal growth and recovery.
Those who want to know more about how these changes are subjectively experienced can read further in our article on the truffle journey. For a deeper look into the effects of psilocybin and psilocin at the cellular level, please refer to the article Psychotherapy in psychedelic therapy is often not necessary. This will give you insight into both the inner experience and the biological basis of these special substances.
Experiencing 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 tripsitter. There are two steps you need to take to make an appointment. The first step is to complete the intake so that we can properly assess your health, intentions and wishes. The second step is to choose and book the session that suits you best, after which we further shape the journey together.
