Psilocybin, the psychoactive compound found in magic mushrooms, is of interest to scientists studying treatments for depression, anxiety, substance use disorders, and some neurodegenerative diseases. Despite its potential therapeutic effects, the strong hallucinogenic effects associated with this compound may limit its scope of use in medicine. In the study published in the ACS Journal of Medicinal Chemistry, scientists created a modified form of psilocin, the active compound produced when psilocybin is processed in the body. In early studies in mice, these new molecules caused less hallucinogen-like effects than pharmaceutical-grade psilocybin, while retaining biological activity.
“Our findings are consistent with a growing body of scientific evidence suggesting that psychedelic effects and serotonergic activity may be uncoupled,” said Andrea Mattalei, corresponding author of the study. “This opens the possibility of designing new treatments that reduce hallucinogenic reactions while preserving beneficial biological activity, potentially enabling safer and more practical treatment strategies.”
Targeting the serotonin pathway in brain disorders
Many mood disorders and neurodegenerative conditions, including Alzheimer’s disease, are associated with disturbances in serotonin, a neurotransmitter that plays an important role in regulating mood and other brain functions. Researchers have spent decades studying psychedelic substances such as psilocybin, which affect serotonin signaling in the brain. However, the hallucinogenic symptoms associated with these compounds may deter some patients from considering them as a treatment, even though they have clear medical benefits.
To address this challenge, a research team led by Sara de Martin, Mattalei, and Paolo Manfredi designed five chemical variants of psilocin. These compounds are designed to release active molecules into the brain more slowly and steadily, potentially reducing hallucinogenic effects while maintaining therapeutic activity.
Testing of new psilocin derivatives
The scientists first evaluated the five compounds in laboratory experiments using human plasma samples and conditions simulating gastrointestinal absorption. These tests helped identify the most promising candidates, known as 4e. The compound showed strong stability during absorption and gradually released psilocin, a property that may help reduce hallucinogenic reactions. At the same time, 4e continued to activate important serotonin receptors at levels similar to psilocin.
The researchers then compared equal doses of 4e and pharmaceutical-grade psilocybin in mice. The substances were administered orally, and the researchers tracked how much psilocin reached the bloodstream and brain over a 48-hour period. In animals treated with 4e, the compound efficiently crossed the blood-brain barrier and produced lower but longer-lasting levels of psilocin in the brain compared to psilocybin.
Behavioral observations revealed another important difference. Mice given 4e had significantly fewer head twitches than mice given psilocybin, which scientists use as a reliable indicator of psychedelic activity in rodents. This occurred despite the strong interaction of 4e with serotonin receptors. Researchers believe this difference is primarily related to how much psilocin is released in the brain and how quickly that release occurs.
Aiming for a psychedelic drug without hallucinations
The researchers say these findings show that it may be possible to design stable psilocin-based compounds that reach the brain and activate serotonin receptors while reducing the strong mind-altering effects commonly associated with psychedelics. Further research will be needed to understand exactly how these molecules work and fully examine their biological effects before scientists can assess their safety and therapeutic potential in people.
The authors acknowledge funding from MGGM Therapeutics, LLC in collaboration with NeuroArbor Therapeutics Inc. Several authors have declared themselves inventors of patents related to psilocin.
