Psilocybin — the psychoactive compound in “magic mushrooms” — is gaining scientific attention for its potential in treating neuropsychiatric conditions including depression, anxiety, substance use disorders and certain neurodegenerative diseases. However, its hallucinogenic effects may limit broader therapeutic applications. Researchers publishing in ACS’ Journal of Medicinal Chemistry synthesized modified versions of psilocin, the active form of psilocybin, that retained their activity while producing fewer hallucinogenic-like effects than pharmaceutical-grade psilocybin in a preliminary study in mice.

“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,” says Andrea Mattarei, a corresponding author of the study.   

Mood disorders and some neurodegenerative diseases, such as Alzheimer’s disease, involve imbalances of the neurotransmitter molecule serotonin, which helps regulate mood and other brain functions. For decades, scientists have been investigating the therapeutic use of psychedelics such as psilocybin on serotonin-signaling pathways. However, the hallucinations that can accompany these drugs may make people wary of taking them, even if there is a medical benefit. 

So, a team led by Sara De Martin, Mattarei and Paolo Manfredi chemically engineered five psilocin derivatives for slower, sustained and potentially non-hallucinogenic release into the brain. They first tested these five compounds using human plasma samples and laboratory conditions mimicking gastrointestinal absorption. These experiments allowed the team to identify a compound they named 4e as the most promising candidate because it displayed favorable stability for absorption and enabled a gradual release of psilocin — a feature that could potentially mitigate hallucinogenic effects. Importantly, 4e retained activity at key serotonin receptors at levels comparable to psilocin. 

Next, the researchers compared the effects of equivalent doses of 4e with pharmaceutical-grade psilocybin in mice. The team administered the compounds orally to mice and measured how much psilocin reached the bloodstream and brain over a 48-hour period. In mice dosed with 4e, the compound was able to cross the blood–brain barrier effectively and exhibited a lower but more sustained presence of psilocin in their brains compared to those treated with psilocybin. When the researchers looked at mouse behavior, they observed that 4e-treated animals exhibited significantly fewer head twitches — a well-established marker of psychedelic-like activity in rodents — than those receiving psilocybin, despite the strong serotonin receptor activity of 4e. This behavioral difference appeared to be associated primarily with the amount and timing of psilocin released in the brain.  

The researchers say their findings demonstrate the feasibility of developing stable brain-penetrating psilocin derivatives that retain serotonin receptor activity while reducing acute mind-altering effects. Further studies will be needed to clarify their mechanism of action and fully characterize their biological effects before assessing their therapeutic potential and safety in humans.  

The authors acknowledge funding from MGGM Therapeutics, LLC, in collaboration with NeuroArbor Therapeutics Inc. Several authors declare they are inventors on patents related to psilocin.  

(Newswise/HG)