Researchers publishing in the American Chemical Society's Journal of Medicinal Chemistry have synthesized chemically modified versions of psilocin - the active form of psilocybin, the psychoactive compound in "magic mushrooms" - that retained biological activity while producing fewer hallucinogenic-like effects than pharmaceutical-grade psilocybin in mice. The work is preliminary, but it targets one of the main obstacles to using psychedelics as medicine.
Psilocybin has drawn serious scientific interest as a possible treatment for depression, anxiety, substance use disorders and certain neurodegenerative diseases. Mood disorders and some neurodegenerative conditions, including Alzheimer's disease, involve imbalances in serotonin, the neurotransmitter that helps regulate mood and other brain functions, and psychedelics act on serotonin-signaling pathways. The hallucinations that come with these drugs, though, make many people reluctant to take them even when a medical benefit is on offer, and they complicate how and where such treatments could be delivered.
The team, led by Sara De Martin, Mattarei and Paolo Manfredi, engineered five psilocin derivatives designed for slower, sustained release into the brain. Testing them in human plasma samples and in laboratory conditions that mimic absorption in the gastrointestinal tract, the researchers singled out one compound, named 4e, as the most promising: it showed favorable stability for absorption and released psilocin gradually, a property that could blunt hallucinogenic effects. Crucially, 4e held onto activity at key serotonin receptors at levels comparable to psilocin itself.
According to the researchers, the results fit a growing view that a drug's psychedelic effects and its serotonergic activity can be pulled apart - meaning it may be possible to design therapeutics that keep the useful biology and shed the hallucinations. That would make treatment safer and more practical, though the findings so far rest on laboratory models and a preliminary mouse study, and much more work will be needed before any such compound reaches patients.