Modified psilocybin compounds may treat brain disorders with fewer hallucinations

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.

Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic activity may be dissociated. 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."

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.