Researchers report designing and testing five fluorinated, reversible carbamate derivatives of psilocin—psilocybin’s active metabolite—aimed at reducing acute psychedelic-like effects while preserving key serotonin-receptor activity. In experiments in mice, a lead compound labeled 4e produced lower but longer-lasting brain exposure to psilocin-related activity and triggered fewer head-twitch responses than pharmaceutical-grade psilocybin, according to a study in the Journal of Medicinal Chemistry.
Psilocybin—the psychoactive compound found in so-called “magic mushrooms”—has drawn increased scientific interest as researchers explore potential treatments for conditions including depression, anxiety, substance use disorders and some neurodegenerative diseases. But psilocybin’s intense acute hallucinogenic effects are widely seen as a practical barrier to broader medical use.
In a study published by the American Chemical Society’s Journal of Medicinal Chemistry, a team led by Sara De Martin, Andrea Mattarei and Paolo L. Manfredi reported designing five fluorinated, reversible N-alkyl carbamate derivatives of psilocin, the active compound produced when psilocybin is processed in the body. The goal was to fine-tune how psilocin-related activity emerges in the body and brain, potentially reducing acute psychedelic-like effects.
In laboratory experiments using human plasma and test conditions meant to simulate gastrointestinal absorption, the researchers compared the stability and conversion profiles of the five candidates and identified a lead compound known as 4e. The team reported that 4e combined favorable stability with controlled, partial conversion and also showed serotonergic activity at the 5‑HT2A and 5‑HT2C receptors—targets commonly implicated in psychedelic pharmacology.
The researchers then compared orally administered 4e with pharmaceutical-grade psilocybin in mice, tracking psilocin-related exposure in blood and brain over a 48-hour period. They reported that 4e showed oral bioavailability and crossed the blood–brain barrier efficiently, producing a lower but more sustained brain exposure profile than psilocybin.
Behavioral testing in mice found that animals given 4e displayed significantly fewer head twitches—a widely used rodent proxy for psychedelic-like activity—than animals treated with psilocybin, even as 4e interacted with serotonin receptors. The researchers suggested the reduced head-twitch response was linked to differences in the timing and magnitude of psilocin-related exposure.
“Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic activity may be dissociated,” Mattarei said in a statement accompanying the report. “This opens the possibility of designing new therapeutics that retain beneficial biological activity while reducing hallucinogenic responses, potentially enabling safer and more practical treatment strategies.”
The authors reported funding from MGGM Therapeutics, LLC, in collaboration with NeuroArbor Therapeutics Inc., and said several authors are inventors on patents related to psilocin. The work is preclinical, and the researchers said more studies are needed to clarify mechanisms and evaluate safety and therapeutic potential in people.
