Psilocybin, the psychoactive compound found in ‘magic mushrooms’, has received scientific attention for its potential in the treatment of neuropsychiatric conditions such as depression, anxiety, substance use disorders, and certain neurodegenerative diseases. However, its hallucinogenic effects may limit its broader therapeutic application. Researchers who have published papers in ACS Medicinal Chemistry Journal In preliminary studies using mice, researchers synthesized a modified form of psilocin, the active form of psilocybin. This modified form exhibits fewer hallucinogenic effects than pharmaceutical-grade psilocybin while maintaining activity.
Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic activity may be uncoupled. This opens the possibility of designing new treatments that reduce hallucinatory reactions while preserving beneficial biological activity, potentially enabling safer and more practical treatment strategies. ”
Andrea Mattalei, corresponding author of the study
Some neurodegenerative diseases, such as mood disorders and Alzheimer’s disease, involve an imbalance in the neurotransmitter molecule serotonin, which helps regulate mood and other brain functions. Scientists have been studying the therapeutic use of psychedelics such as psilocybin in the serotonin signaling pathway for decades. However, these drugs can cause hallucinatory symptoms, so even if they have medical benefits, you may be cautious about taking them.
So a team led by Sara de Martin, Mattalei, and Paolo Manfredi chemically engineered five psilocin derivatives into the brain that last longer and may not cause hallucinations. They first tested these five compounds using human plasma samples and laboratory conditions that mimic gastrointestinal absorption. These experiments allowed the researchers to identify a compound they named 4e as the most promising candidate. The reason is that this compound showed favorable stability for absorption and allowed sustained release of psilocin, a feature that may reduce hallucinogenic effects. Importantly, 4e retained activity at key serotonin receptors at levels comparable to psilocin.
The researchers then compared the effects of equal doses of 4e and pharmaceutical-grade psilocybin in mice. The researchers administered the compound orally to mice and measured the amount of psilocin that reached the bloodstream and brain over 48 hours. Mice treated with 4e showed that the compound was able to effectively cross the blood-brain barrier and had a lower but more persistent presence of psilocin in the brain compared to mice treated with psilocybin. When the researchers observed the behavior of mice, they observed that despite 4e’s strong serotonin receptor activity, animals given 4e had significantly fewer head twitches, an established marker of psychedelic activity in rodents, than animals given psilocybin. This behavioral difference appears to be primarily related to the amount and timing of psilocin released in the brain.
The researchers say their findings demonstrate the feasibility of developing stable brain-penetrating psilocin derivatives that maintain serotonin receptor activity while reducing acute mind-altering effects. Further studies will be required to elucidate its mechanism of action and fully characterize its biological effects before evaluating its therapeutic potential and safety in humans.
sauce:
american chemical society
Reference magazines:
Banzato, M., Others. (2026). Design, synthesis, and pharmacokinetic profiling of fluorinated reversible substances N -Alkyl carbamate derivatives of psilocin for subhallucinogenic brain exposure. Journal of Medicinal Chemistry. DOI: 10.1021/acs.jmedchem.5c01797. https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01797
