Binding of Psilocin and Psilocybin to Serotonin Receptors

Binding affinity studies show psilocin and psilocybin have different preferences for serotonin receptors.

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Abundant scientific evidence shows the effects of psychedelic substances like psilocin are mediated via activation of 5-HT2A receptors in the brain,1–6 primarily in the prefrontal cortex.7–9 The abbreviation 5-HT stands for 5-hydroxytryptophan, the chemical name for serotonin. Psilocin (the metabolically active form of psilocybin) is a serotonin agonist. This means it binds to serotonin receptors and produces a physiological effect.

There are seven known classes of the 5-HT receptor with a total of 14 subtypes.10 and psilocin and psilocybin have different affinities for them. When these molecules bind to a receptor, it causes a variety of effects. For example, psilocin binds as an agonist to the 5-HT2A receptor and causes the psychedelic effects magic mushrooms are famous for.

Binding Affinity – The Measure of Separation

Scientists test how well drugs and chemicals bind to receptors by measuring their binding affinity, designated by the symbol Ki. Binding affinity is one kind of dissociation constant. This means that the higher the number, the more likely the substance is to separate from the receptor. Conversely, low binding affinity values mean the substance binds more strongly and is less likely to dissociate from the receptor. These binding affinities are measured in nanomoles (nM). Table 1 shows the binding affinity of psilocin and psilocybin for several 5-HT receptor subtypes.

Table 1: Binding affinities for psilocybin and psilocin at 5-HT receptors.11
ReceptorPsilocybin Ki (nM)Psilocin Ki (nM)Species
5-HT1A>10,000567.4human
5-HT1B>10,000219.6human
5-HT1D2,11936.4human
5-HT1E194.852.2human
5-HT2A>10,000107.2human
5-HT2B98.74.6human
5-HT2C>10,00097.3rat
5-HT3>10,000>10,000human
5-HT56,181.083.7human
5-HT6413.557.0human
5-HT7597.93.5human

There are no data available for 5-HT1F, 5-HT4, 5-HT5A, and 5-HT5B.

Why is This Important?

These data clear up the common misconception that psilocybin is the main active ingredient in magic mushrooms. The table shows that for the 5-HT2A receptor (the one responsible for psychedelic/hallucinogenic effects), psilocybin has a Ki of >10,000 nM and psilocin 107.2 nM. The significantly lower dissociation constant for psilocin means it binds more strongly to the receptor and has a greater effect. Also, note the significantly lower binding affinities for psilocin on other serotonin receptors such as 5-HT1A, 5-HT1B, and 5-HT2C. Scientists do not understand (and are not currently studying) how the binding affinities at all these receptors translate into the effects experienced by people who ingest magic mushrooms containing psilocybin and psilocin.

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