A new “magic mushroom” compound may deliver psychedelic brain benefits without the trip.
Psilocybin, the psychoactive ingredient in “magic mushrooms,” is attracting increasing interest from scientists studying treatments for neuropsychiatric conditions such as depression, anxiety, substance use disorders, and certain neurodegenerative diseases. While research suggests the compound may have therapeutic value, its strong hallucinogenic effects could limit how widely it is used in medicine.
In a study published in ACS’ Journal of Medicinal Chemistry, researchers developed modified forms of psilocin, the active compound produced from psilocybin in the body. In early experiments with mice, these altered molecules maintained biological activity but triggered fewer hallucinogenic-like effects than pharmaceutical-grade psilocybin.
“Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic activity may be dissociated,” says Andrea Mattarei, a corresponding author of the study. “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.”
Psilocybin, Serotonin, and Brain Health
Mood disorders and some neurodegenerative diseases, including Alzheimer’s disease, are linked to disruptions in serotonin, a neurotransmitter that plays an important role in regulating mood and many other brain functions. Because psilocybin influences serotonin signaling pathways, scientists have spent decades studying whether psychedelic compounds might help treat these conditions. However, the intense hallucinations sometimes caused by these drugs may discourage patients from using them, even when there could be clear medical benefits.
Designing New Psilocin Derivatives
To address this challenge, a research team led by Sara De Martin, Mattarei, and Paolo Manfredi created five chemically modified versions of psilocin. These compounds were designed to release the active molecule more gradually in the brain, potentially reducing psychedelic effects while preserving therapeutic activity.
The scientists first evaluated the compounds using human plasma samples and laboratory models that simulate gastrointestinal absorption. These tests helped identify the most promising candidate, a compound called 4e. The molecule showed strong stability during absorption and released psilocin slowly over time, which could help limit hallucinogenic effects. At the same time, 4e maintained activity at important serotonin receptors at levels similar to psilocin.
Mouse Experiments Show Reduced Psychedelic-Like Effects
Researchers then compared equivalent doses of 4e and pharmaceutical-grade psilocybin in mice. The compounds were given orally, and the team measured how much psilocin reached both the bloodstream and the brain during a 48-hour period. In animals treated with 4e, the compound successfully crossed the blood–brain barrier and produced lower but longer-lasting levels of psilocin in the brain compared with psilocybin.
Behavioral observations revealed another important difference. Mice that received 4e showed far fewer head twitches than mice treated with psilocybin. In rodent studies, head twitch behavior is widely used as an indicator of psychedelic-like activity. This reduced response occurred even though 4e still strongly activated serotonin receptors. The researchers suggest that the difference likely relates to the amount of psilocin reaching the brain and the timing of its release.
Toward Psychedelic Inspired Therapies Without the Trip
According to the researchers, the findings show that it may be possible to create stable psilocin-based compounds capable of reaching the brain and activating serotonin receptors while limiting strong mind-altering effects. Additional research will be required to better understand how these compounds work and to evaluate their full biological impact before testing their safety and therapeutic potential in humans.
Reference: “Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N-Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure” by Marco Banzato, Martina Colognesi, Lorena Lucatello, Stefano Comai, Gianfranco Pasut, Francesca Capolongo, Laura Orian, Lucia Biasutto, Anna Signor, Daniela Gabbia, Paolo L. Manfredi, Sara De Martin and Andrea Mattarei, 26 January 2026, Journal of Medicinal Chemistry.
DOI: 10.1021/acs.jmedchem.5c01797
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.
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