Mar 21, 2026
3 min read
A modified version of psilocin may provide a way to treat certain mental illnesses, without the hallucinatory side effects.
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Scientists from the University of Padova (Italy) have synthesized a modified version of psilocin, the active form of psilocybin, which retains the promise of drug treatment while reducing the hallucinogenic effects often associated with it.In a rat study, they report the design, production and evaluation of a library of compounds that may open up new possibilities for psychedelic treatments.
A growing body of evidence suggests a key role for serotonin signaling pathways in modulating neuroplasticity, a process that has therapeutic implications for a range of neuropsychiatric conditions, including depression, anxiety, substance use disorders, and neurodegenerative diseases.For decades, researchers have studied how psychedelics like psilocybin affect these pathways in rodents and whether they can be used to treat the aforementioned diseases in humans.However, their potential medical benefits are outweighed by acute psychoactive effects.
To circumvent this obstacle, the group designed five fluorinated reversible N-alkyl carbamate derivatives of xylosine with limited hallucinogen-like effects.By changing the number and position of fluorine atoms on the alkyl bromide part, they managed to change the stability of the carbamate bond.
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The resulting substances, compounds 4a-e, were tested in vitro models reproducing the pH conditions of the gastrointestinal tract.During these experiments, compound 4e stood out, offering a good balance between chemical stability, metabolic protection and controlled release, and was therefore selected as a leading candidate.
In vitro analysis of compound 4e using Chinese hamster ovary cells expressing serotonin receptors 5-HT2A and 5-HT2C showed that it acts as a selective partial agonist of both receptors and its serotonergic profile matches that of psilocin.
In addition, the team conducted in vivo studies in mice, providing insight into the pharmacokinetic, pharmacodynamic and toxicological profiles of 4e.After oral administration, they measured plasma and brain concentrations of the drug for 48 hours, indicating its rapid systemic absorption and ability to cross the blood-brain barrier.Compared to psilocybin, 4e was associated with significantly lower systemic psilocin exposure, suggesting that it may reduce the risk of harmful hallucinogenic effects.
The researchers then looked at mouse behavior, analyzing the head-bobbing response—a well-established sign of psychedelic activity in rodents—in animals given psilocybin or compound 4e.There were significantly more head hits compared to the control group, and 4e appeared to produce a delayed and dampened behavioral response.
In addition, compound 4e was well tolerated in toxicological tests performed after a single oral administration of a high dose in rats, chosen due to their established translational value in toxicology studies.
In general, these studies show, although they are preliminary, the ability of this platform to produce psilocin products for stabilization and perhaps even unconscious release in the brain.
“Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic effects can be separated,” commented Andrea Mattarei, corresponding author of the study.“This opens the possibility of designing new therapies that retain beneficial biological activity while reducing hallucinogenic responses, potentially enabling safer and more practical treatment strategies.”
