[Solved] Psilocybin effect on the insula

Psilocybin is the active ingredient in magic mushrooms and truffles. In your body, it is converted into psilocin, a molecule that binds to certain serotonin receptors (especially the 5-HT₂A receptors). These are common in the insula – an important brain area involved in how you feel your body, how you experience emotions, and how you perceive 'yourself'.

The insula works closely with the anterior cingulate cortex in what the salience network is mentioned. This network helps you determine which stimuli (thoughts, emotions, body signals) are important. Due to the action of psilocin, the balance in this network temporarily changes, which you may notice as a different sense of time, self, and sensory perception.

Animal research shows that the insula during a trip more active becomes. Certain genes (such as c-Fos and Egr-1) which are activated when brain cells are active, rise in areas such as the insular cortex, but also in the touch, hearing, and visceral brain regions. This explains why touches, sounds, and sensations often feel more intense or emotional during a trip.

At the same time, the anterior part of the insula (which is also involved in fear) seems to actually less active to become. During research on mice, this led to fewer stress responses, which aligns well with the sense of calm and acceptance that many people experience during a psilocybin session.

At the molecular level, even more is happening. Psilocybin influences genes that ensure communication between brain cells, such as Grin2a, Grin2b (glutamate) and Htr2a (serotonin). In addition, genes related to are activated. brain growth and repair, such as BDNF and mTOR. Although there is no evidence that new brain cells arise in the insula, it is likely that connections between existing cells become stronger and reorganize.

Similar effects have been found in humans. For example, an fMRI study showed that people with BDD (body dysmorphia) improved after psilocybin, and that this was associated with stronger connections between the prefrontal cortex and the anterior insula. In another study, it was found that the insula responded more strongly to emotional stimuli one week after ingestion, but that this normalized again after four weeks. This fits the idea that psilocybin induces a period of heightened sensitivity and self-insight, followed by calm and integration.

In summary: Psilocybin influences the insula on multiple levels: it activates receptors, temporarily increases brain activity, and initiates processes that can restructure brain networks. This can lead to a deeper connection with your body and emotions, and ultimately to greater inner balance.

Would you like to experience for yourself what this can do for you? Then you can start with a no-obligation intake for psychedelic therapy and discover whether a truffle session suits you.

Psilocybin is rapidly absorbed after oral intake dephosphorylated to psilocin. Psilocin is a partial agonist of 5‑HT₂A‑receptors (5‑hydroxytryptamine 2A) with affinity for other serotonin and dopamine receptors. The insula Together with the dorsal anterior cingulate cortex, it forms the core of the salience network and is important for interoception, emotion, and self-awareness. The insula has a high density of 5-HT₂A receptors and glutamate receptors and receives serotonergic and dopaminergic projections; this makes the area particularly sensitive to psychedelics.

Neurochemistry and receptor mechanisms

1. 5‑HT₂A‑receptors: Psilocin binds to 5‑HT₂A‑receptors on excitatory cortical neurons. A PET study with [¹¹C]MDL‑100,907 showed that after 10 mg psilocybin, the average 5‑HT₂A‑receptor occupancy in the cortex is approximately 40 % (individually varying from ~20–75 %) and that regions with the highest occupancy were the subgenual anterior cingulate (part of the DMN) and intraparietal sulcus. The insula was not specifically highlighted, but the study shows that psilocybin achieves broad cortical 5‑HT₂A‑occupancy.

2. Serotonergic modulation of the salience network: The salience network (anterior insula & dorsal ACC) detects relevant stimuli and switches between the default-mode network (DMN) and the central executive network. Activation of 5‑HT₂A‑receptors by psilocin can shift the balance within this network and thereby alter interoceptive and emotional processing.

3. Interaction with glutamatergic and dopaminergic systems: Whole-brain c-Fos mapping linked psilocybin-induced c-Fos expression to the expression of NMDA receptor subunits Grin2a and Grin2b and to the 5‑HT₂A‑ gene Htr2a. This correlation suggests that serotonergic agonism enhances glutamatergic activity. Additionally, general reviews show that dopaminergic modulation of GABA interneurons in the mPFC-ACC-insula complex regulates the gamma oscillations important for self-awareness; psilocybin can influence this system via indirect dopaminergic activation.

4. Other neurotransmittersMicrodialysis studies show increases in extracellular dopamine in the nucleus accumbens and serotonin in the mPFC after psilocybin. However, there is no specific microdialysis study in the insula. Functional studies suggest that psilocybin affects the insula via serotonergic and glutamatergic pathways, leading to an altered excitation/inhibition balance and an altered state of consciousness.

Gene expression and molecular changes

Immediate early genes (IEGs)

1. c‑Phos‑expression: In a mouse study comparing psilocybin with ketamine, psilocybin led to higher c‑Fos‑expression in the dorsal agranular insular cortex (AId) compared with ketamine. This IEG response was associated with strong expression of Grin2a, Grin2b and Htr2a. A recent follow-up study in which psilocybin was administered in an open field or enriched environment (TRAP2 mouse line) reported that psilocybin in eight cortical clusters—including somatosensory, motor, visceral, auditory, gustatory and insular cortex—c‑Fos‑density increased. This indicates strong activation of neocortical networks, including the insula, while subcortical structures were suppressed.

2. c-Fos reductionIn contrast to this, a UNC thesis on psilocin showed that a single intraperitoneal injection (2 mg/kg) increased c-Fos expression. reduced in the global insular cortex (p = 0.039), especially in the anterior insula. Subregional analyses showed a significant decrease in c‑Fos in the agranular anterior insula (AIC). This paradox (higher vs. lower c‑Fos) reflects differences in dosage, route of administration, and time of measurement.

3. ECG-1 and other IECs: A rat study reported that 1 mg/kg psilocybin the BOLD activity and Egr‑1 (an IEG associated with synaptic plasticity) increased in somatosensory, auditory, visual, and insular cortex, indicating widespread cortical activation during the acute psychedelic state. In the same study, BOLD activity normalized after 24 hours, while glutamate and N-acetylaspartate metabolites decreased in the ACC. This is early evidence that acute hyperactivation transitions into later hypoactivity.

Neuroplasticity and long-term gene expression

1. Neuroplastic markersPreclinical studies show that psilocybin increases the expression of plasticity-related genes within 24 hours, including BDNF, mTOR, GAP‑43, TrkB and synaptophysin in the hippocampus, amygdala, and prefrontal cortex. Although the insula has not been directly studied, a review mentioned that psilocybin plasticity-related transcription strongly upregulates in most cortical regions, including the insula, which points to similar structural changes.

2. Structural changes: Psilocybin induces dendritogenesis and synaptogenesis in the hippocampus and frontal cortex. Dendritic spines become longer and more numerous, and new synapses are retained for at least a week. There are no direct data for the insula, but since this region is rich in 5‑HT₂A‑receptors and is involved in salience network connections, it is plausible that similar plasticity occurs. Moreover, the insula receives strong projections from the anterior cingulate cortex, which is plastically influenced by psilocybin.

Neurogenesis

1. Hippocampus and neocortex: Psilocybin promotes hippocampal neurogenesis and increases markers such as doublecortin and BrdU, with behavioral effects such as improved learning and stress resistance. In the prefrontal cortex, increased expression of neurogenesis marker Doublecortin and synaptogenesis proteins have been reported. There is no direct evidence for increased neurogenesis in the insula. However, the insula is an allocortical region with typically limited postnatal neurogenesis; therefore, the contribution of psilocybin likely consists of synaptic restructuring rather than new neurons.

Acute changes in insular activity

Animal models

1. Global activation: In mice and rats, psilocybin causes a within 1–2 hours hypercortical state, characterized by increased BOLD activity and IEG expression in the sensory and insular cortex. A c-Fos mapping study found increased c-Fos activity in the dorsal agranular insula (AId), while subcortical nuclei such as the raphe showed less c-Fos. In a context-dependent mouse study, motor, visceral, auditory, gustatory and insular areas activated.

2. Reduced activity in anterior insula: The UNC thesis showed precisely a decrease of c-Fos in the agranular anterior insula (AIC) after psilocin injection. Fiber photometry showed that the AIC normally responds strongly to aversive air puffs; psilocin reduced this c-Fos response and decreased fecal boli during stress—a sign of anxiolytic (anxiety-reducing) action. With this, the study suggests that psilocin suppresses certain insula subregions, which could explain the anxiolysis and subjective calmness during a trip.

Human imaging

1. Functional connectivity: An open-label fMRI study in patients with body dysmorphic disorder (BDD) who received 25 mg of psilocybin showed that increased functional connectivity between the lateral prefrontal cortex and the anterior insula predicted the reduction of clinical symptoms one week after administration. This coupling between the executive network and the salience network was interpreted as a neurobiological mechanism for improved cognitive insight and reduced self-criticism. A reduction in connectivity between the default-mode network and the salience network was also observed, but this trend was no longer significant at 12 weeks.

2. BOLD response during emotional tasksA longitudinal study in which healthy volunteers received a high dose of psilocybin showed that one week after administration the BOLD response during an emotional conflict (Stroop task) increased in a network that the left anterior insula included. One month later, the responses in this insula cluster had decreased again. The finding supports an acutely heightened (and later normalizing) response to emotional stimuli, possibly related to heightened interoceptive awareness during the trip.

3. Claustrum vs insula connectivity: An fMRI study in which psilocybin investigated the function of the claustrum found that psilocybin the connectivity between the frontoparietal control network and the claustrum reduced more strongly than between that network and the insula. There were no significant changes in amplitude or variability of fMRI signals in the insula itself, suggesting that the insula is less susceptible to acute desynchronization than the claustrum.

Long-term changes and plasticity

1. Functional connectivity months later: In the BDD study, changes in lPFC insula connectivity remained trend-like after 12 weeks, but not significant. This suggests that connectivity adjustments in the insula are primarily subacute intervene and then normalize.

2. BOLD response 1 month after psilocybinThe emotional Stroop study reported that BOLD responses in the anterior insula were lower one month after administration than at one week. This may indicate prolonged homeostatic inhibition or recovery.

3. Gene expression and synaptic plasticity: Preclinical data show that psilocybin long-term (≥ 10 days) affects the expression of synaptic proteins such as GAP‑43 and synaptophysin increases in hippocampus, amygdala and frontal cortex. While no specific insula data are available, it is believed that the insula likely benefits from this plasticity via its frontal and limbic connections. The UNC thesis reported that the anterior insula has high 5-HT₂A density and strong input from the ACC; as a result, the insula can undergo structural changes via transsynaptic plasticity.

Summary discussion

1. Neurochemistry – Psilocybin is converted to psilocin, which primarily activates 5‑HT₂A‑receptors but also acts directly or indirectly on 5‑HT₁A, 5‑HT₂C, dopaminergic D2‑receptors, and TAAR1. The insula has a high density of 5‑HT₂A‑receptors and receives serotonergic and dopaminergic input, causing psilocybin to cause strong modulation of excitation/inhibition in this area. PET studies show substantial 5‑HT₂A‑receptor occupancy in the cortex after psilocybin.

2. Gene expression – Psilocybin/psilocin can both increase in c-Phos (in dorsal agranular insula and neocortex) as c-Fos reduction (in agranular anterior insula) cause, depending on dose, timing, and context. Transcript analyses show a relationship with glutamate receptor genes (Grin2a/b) and the 5‑HT₂A‑gene (Htr2a), which points to the interplay of serotonergic and glutamatergic signaling. Furthermore, psilocybin is associated with the upregulation of plasticity genes (BDNF, mTOR, TrkB, GAP‑43, synaptophysin), enabling long-term structural changes.

3. Neurogenesis and structure – Psilocybin promotes dendritogenesis, synaptogenesis, and hippocampal neurogenesis, but there is no direct evidence for neurogenesis in the insula. Synaptic reorganization in ACC-insula circuits may contribute to long-lasting therapeutic effects.

4. Acute activity – In animal models, psilocybin leads to hyperactivation of sensory and insular cortices (increased BOLD, c-Fos, Egr-1), whereas some insula subregions (anterior agranular insula) show decreased c-Fos expression with anxiolytic behavioral outcomes. In humans, increased lPFC-anterior insula connectivity predicts subacute symptom improvement after psilocybin, and BOLD signaling in the insula peaks one week after administration but declines after one month.

5. Long-term effects – Functional and plasticity changes in the insula appear to be largely subacute: connectivity and BOLD reactivity normalize within weeks to months, while underlying synaptic restructuring may persist longer. Preclinical studies show that psilocybin permanently increases the expression of neuroplasticity genes; through strong interaction with ACC circuits, this can indirectly influence the insula.

Conclusion

The insular cortex plays a central role in the processing of interoception, emotion, and self-awareness and is rich in 5‑HT₂A‑receptors. Psilocybin/psilocin influences the insula via serotonergic and glutamatergic systems, leading to complex changes in activity and gene expression. Acute administration typically increases IEG expression and BOLD activity in the (dorsal) insula but may suppress activity in some subregions (anterior insula) and induce anxiolytic inhibition. The degree of functional connectivity between the insula and frontal networks predicts subacute therapeutic effects in patients. Long-term effects include synaptic restructuring and increased expression of plasticity genes, but functional changes appear to diminish within a month. Although there is little evidence for insula-specific neurogenesis, the combination of acute activation and long-term plasticity points to an important role of the insula in the subjective and therapeutic effects of psilocybin.