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Psychedelic research needed to explain why a mushroom-derived compound reliably produces altered perception, and the answer lies in which receptor it activates in the cortex. For example, pre-treating a volunteer with a drug that blocks this receptor abolishes the hallucinogenic effect of psilocybin, strong evidence for the receptor's central role. Psilocybin connects to a much bigger serotonin-receptor story that also explains other classic psychedelics and some antipsychotic drug targets.

Psilocybin is a prodrug, after ingestion it is rapidly dephosphorylated to its active metaboliteA breakdown product of a drug that is itself still able to produce an effect in the body.Read more →, psilocin. Psilocin acts as an agonistA drug or chemical that activates a receptor to produce an effect.Read more → at the serotonin 2A receptor, the 5-HT2AA serotonin receptor subtype that many antipsychotic drugs block, thought to help their antidepressant and antipsychotic effect.Read more → receptor, predominantly on layer 5 pyramidal neurons in the cortex, especially the prefrontal cortexThe front part of the brain responsible for planning, judgement and controlling impulses.Read more →. Agonism at this receptor increases excitatory glutamate signalling in cortical circuits and alters normal patterns of large-scale brain network connectivity. This altered connectivity is thought to underlie the perceptual and cognitive changes reported during a psychedelic experience.

The stem describes a hallucinogenic mushroom compound, its active metaboliteA breakdown product of a drug that is itself still able to produce an effect in the body.Read more →, or an experiment where a drug blocks its subjective effects, and asks for the receptor responsible.

Distinguish psilocybin's mechanism, 5-HT2AA serotonin receptor subtype that many antipsychotic drugs block, thought to help their antidepressant and antipsychotic effect.Read more → receptor agonism, from that of classic monoamine-reuptake antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability rather than directly agonising a specific receptor subtype. Distinguish 5-HT2A receptor agonism from 5-HT1AA serotonin receptor subtype whose partial activation is linked to reducing anxiety.Read more → receptor agonism, a different serotonin receptor subtype relevant to buspirone, an anti-anxiety medication, rather than to psychedelic effects.

Trap, assuming psilocybin itself, rather than its active metaboliteA breakdown product of a drug that is itself still able to produce an effect in the body.Read more → psilocin, is what binds the receptor. Resolution: psilocybin is a prodrugA drug that is inactive until the body converts it into its active form.Read more → that is rapidly converted to psilocin, and it is psilocin that acts as the 5-HT2AA serotonin receptor subtype that many antipsychotic drugs block, thought to help their antidepressant and antipsychotic effect.Read more → receptor agonistA drug or chemical that activates a receptor to produce an effect.Read more →. Trap: confusing the 5-HT2A receptor with the 5-HT1AA serotonin receptor subtype whose partial activation is linked to reducing anxiety.Read more → receptor. Resolution: 5-HT2A receptor agonism on cortical pyramidal neurons drives psilocybin's psychedelic effect, while 5-HT1A receptor activity is linked to different drugs, such as buspirone's anti-anxiety action.

When a question names a psychedelic compound and asks for its receptor target, default to the 5-HT2AA serotonin receptor subtype that many antipsychotic drugs block, thought to help their antidepressant and antipsychotic effect.Read more → receptor; if the question instead names a drug that blocks the effect, recognise ketanserin as the discriminating clue confirming the same receptor.