Researchers have been exploring the use of psilocybin, the psychoactive ingredient in "magic mushrooms," as a treatment for several neuropsychiatric conditions such as depression, anxiety, substance use disorders, and some neurodegenerative diseases. However, its hallucinogenic effects present challenges for broader therapeutic application.
A team led by Sara De Martin, Mattarei, and Paolo Manfredi published findings in the Journal of Medicinal Chemistry describing the synthesis of five modified versions of psilocin, which is the active form of psilocybin. These new compounds were designed to release more slowly and potentially reduce hallucinogenic effects while maintaining activity at serotonin receptors.
The researchers first tested these derivatives using human plasma samples and laboratory simulations of gastrointestinal absorption. Through this process, they identified one compound, labeled 4e, as particularly promising due to its stability for absorption and gradual release profile. According to the research team, "4e retained activity at key serotonin receptors at levels comparable to psilocin."
In animal studies involving mice, the team compared oral doses of 4e with pharmaceutical-grade psilocybin. They measured how much psilocin entered the bloodstream and brain over a 48-hour period. Mice treated with 4e showed effective crossing of the blood–brain barrier and maintained a lower but more sustained level of psilocin in their brains than those given psilocybin.
Behavioral analysis revealed that mice receiving 4e had significantly fewer head twitches—a recognized indicator of psychedelic-like activity in rodents—than those treated with traditional psilocybin. The researchers noted that "this behavioral difference appeared to be associated primarily with the amount and timing of psilocin released in the brain."
The study's authors stated: "Their findings demonstrate the feasibility of developing stable brain-penetrating psilocin derivatives that retain serotonin receptor activity while reducing acute mind-altering effects." They also emphasized that further research will be needed to understand these compounds' mechanisms and assess their safety before considering clinical use in humans.
