Psilocybin is a compound found in specific mushroom species, recognized for its effects on consciousness. When consumed, it interacts with the brain’s communication network by engaging with specialized proteins known as receptors. This interaction allows a substance derived from a fungus to modulate the intricate signaling systems that govern human perception and thought.
Psilocybin’s Conversion to Psilocin
Before any psychological effects can occur, psilocybin must undergo a chemical transformation within the body. Upon ingestion, the psilocybin molecule encounters enzymes, particularly alkaline phosphatases, which are present in the intestines, kidneys, and blood. These enzymes efficiently remove a phosphate group from psilocybin in a process called dephosphorylation. This metabolic step converts psilocybin, which is biologically inactive, into its pharmacologically active form: psilocin.
This resulting molecule, psilocin, is more fat-soluble, or lipophilic, than its precursor. This increased lipophilicity is a property that allows it to more readily pass through the protective blood-brain barrier.
The Serotonin System and its Receptors
The brain operates using a network of chemical messengers called neurotransmitters, and one of the most significant of these is serotonin, or 5-hydroxytryptamine (5-HT). This neurotransmitter is integral to a wide array of functions, including the regulation of mood, appetite, sleep, learning, and sensory perception. The brain’s serotonin system is a complex web of pathways that release serotonin into the spaces between nerve cells, allowing them to communicate.
To receive these serotonin signals, the brain is equipped with a family of proteins known as serotonin receptors. There are at least 14 subtypes of these receptors, grouped into seven families (5-HT1 through 5-HT7). Each receptor subtype is distributed differently throughout the central and peripheral nervous systems and, when activated by serotonin, can produce either excitatory or inhibitory effects on neurons.
The Key Interaction with the 5-HT2A Receptor
The psychological effects of psilocybin are primarily initiated by the interaction of its active form, psilocin, with a specific type of serotonin receptor: the 5-HT2A receptor. The molecular structure of psilocin is similar to that of serotonin, which allows it to fit into the same receptors. While psilocin binds to several types of serotonin receptors, its highest affinity is for the 5-HT2A subtype, where it acts as a partial agonist, meaning it activates the receptor but not to the same maximum extent as serotonin itself.
These 5-HT2A receptors are most densely concentrated in high-level processing areas of the brain, particularly in the cerebral cortex. Regions like the prefrontal cortex, which is involved in complex cognition, perception, and sense of self, are rich in these receptors. The intensity of the subjective psychedelic experience has been directly correlated with the degree to which psilocin occupies these 5-HT2A receptors in the brain.
Downstream Brain Effects of Receptor Activation
Once psilocin binds to and activates the 5-HT2A receptors, it sets off a chain reaction of neurobiological events. This activation, primarily in layer V pyramidal neurons of the prefrontal cortex, increases the excitability of these cells. This initial effect does not remain localized; instead, it leads to broad, system-level changes in brain communication. One of the most significant consequences is the alteration of functional connectivity, changing how different brain regions and large-scale networks communicate with one another.
A network affected is the Default Mode Network (DMN), a collection of brain areas that is most active during inward-focused thought, such as self-reflection and mind-wandering. Psilocybin administration is associated with a decrease in DMN activity and integrity. This disruption of the DMN is thought to be directly linked to the subjective experience of “ego dissolution” or a temporary loss of the sense of self. Simultaneously, connectivity between other networks, such as those involved in sensory processing, becomes more integrated, which may explain altered perceptions and synesthesia.
Role of Other Receptors
While the 5-HT2A receptor is the principal target for psilocin’s psychedelic effects, it is not the only receptor involved. Psilocin also binds with varying affinities to several other serotonin receptor subtypes, including 5-HT1A, 5-HT2C, and others. The interaction with these additional receptors likely contributes to the full spectrum of the drug’s effects, modulating the experience in subtle but meaningful ways.
For instance, activation of the 5-HT1A receptor is associated with anxiolytic (anxiety-reducing) and antidepressant-like effects. Its engagement may help to influence the emotional tone of the experience. The 5-HT2C receptor is also implicated, and its interaction could play a role in the complex changes to mood and appetite. Furthermore, at higher concentrations, psilocin can interact with dopamine receptors, although with much lower affinity.