‘Magic mushroom’ derivative could heal without hallucinations, sparking hope for new therapies
A not-so-trippy ‘magic mushroom’-derived compound may offer a way of treating certain neuropsychiatric conditions, without hallucinatory side effects.
Scientists from the University of Padova (Italy) have synthesized a modified version of psilocin, the active form of psilocybin, which maintains the drug’s therapeutic promise while minimizing the hallucinogenic effects with which it is usually associated. In a study in mice, they report the design, synthesis and evaluation of a library of compounds that may open up new psychedelic treatment options.
A growing body of evidence suggests a key role of serotonin signaling pathways in modulating neuroplasticity – a process with therapeutic implications for a range of neuropsychiatric conditions, including depression, anxiety, substance use disorders and neurodegenerative diseases. For decades, researchers have been studying how psychedelics, like psilocybin, affect these pathways in rodents and whether they could be used to treat the aforementioned conditions in humans. However, their potential medical benefits are offset by acute psychoactive effects.
To try and circumvent this roadblock, the team engineered five fluorinated reversible N-alkyl carbamate derivatives of psilocin with limited hallucinogenic-like effects. By varying the number and positioning of fluorine atoms on the alkyl promoiety, they were able to alter carbamate bond stability.
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The resulting substances, compounds 4a–e, were then tested in in vitro models that reproduced the pH conditions of the gastrointestinal tract. During these experiments, compound 4e stood out, offering the best compromise between chemical stability, metabolic protection and controlled release, and as a result was selected as the lead candidate.
Further in vitro analysis of compound 4e, using Chinese hamster ovary cells overexpressing key serotonin receptors 5-HT2A and 5-HT2C, revealed that it acts as a selective partial agonist at both receptors and that its serotonergic profile closely mirrors that of psilocin.
In addition, the team conducted in vivo studies in mice, offering insights into compound 4e’s pharmacokinetic, pharmacodynamic and toxicological profiles. Following oral administration, they measured the levels of the drug in plasma and brain over a 48-hour period, demonstrating its rapid systemic absorption and ability to cross the blood–brain barrier. When compared to psilocybin, 4e was associated with significantly lower systemic psilocin exposure, suggesting it may offer a reduced risk of acute hallucinogenic effects.
The researchers then took a look at mouse behavior, analyzing the head-twitch response – a well-established marker of psychedelic-like activity in rodents – in animals given psilocybin or compound 4e. Psilocybin elicited a significantly higher number of head-twitches relative to the control, while 4e appeared to produce a delayed and attenuated behavioral response.
In addition, compound 4e was well tolerated in a toxicological assessment conducted following a single oral administration at a high dose in rats, chosen for their established translational relevance for toxicology studies.
Collectively, these findings demonstrate, albeit preliminarily, the potential of this platform to develop psilocin derivatives for sustained and maybe even non-psychoactive release into the brain.
“Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic activity may be dissociated,” commented 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.”