Study Finds Norpsilocin is More Potent Than Psilocin at 5-HT2A

This is the first scientific evidence that anything but psilocybin or psilocin could potentially contribute to the pharmacology of magic mushrooms.

February 2020

In a February 2020 study published in the Journal of Natural Products, Sherwood et al. describe their work synthesizing and studying four lesser-known magic mushroom (aka psilocybin mushroom) compounds; aeruginascinnorpsilocin, baeocystin, and norbaeocystin.1

The authors tested norpsilocin to see if it activated the serotonin 5-HT2A receptor by using a test that measures the Gq-mediated calcium flux at 5-HT2A. The data indicated that compared to psilocin, norpsilocin was almost a full agonist at the mouse and human 5-HT2A receptor. The authors stated,

Norpsilocin was thus as potent if not more efficacious compared to psilocin…

Chemically, norpsilocin has one methyl group on the terminal nitrogen, while psilocin has two. Norpsilocin is also the metabolite resulting from the dephosphorylation of baeocystin.

The Sherwood et al. study also found that baeocystin did not elicit the head twitch response (HTR) in mice. They theorized that this inactivity might be due to baeocystin not being able to cross the blood-brain barrier. So, the next question became, if inactive baeocystin is metabolized to bioactive norpsilocin in the body, then why doesn’t administering baeocystin cause the HTR in mice?

The authors attribute the lack of activity by norpsilocin in the HTR test to the action of monoamine oxidase enzymes (MAO). MAOs use oxygen atoms to remove amine groups from molecules. They noted that secondary amines tend to be broken down readily by MAOs compared to tertiary amines.2 Therefore, they hypothesized that norpsilocin (secondary amine) gets degraded faster in the body compared to psilocin (tertiary amine).

This landmark study is the first biological testing of norpsilocin in a laboratory setting. Learning that it is more potent at 5-HT2AR than psilocin is an intriguing finding for further investigation.