Summary: While psilocybin is hailed as a breakthrough for depression and anxiety, many patients remain wary of the intense “trips” associated with the drug. Now, researchers have engineered modified versions of psilocin (the active form of psilocybin) that offer the therapeutic benefits of mushrooms without the hallucinogenic side effects.
By creating a specific derivative named 4e, the team achieved a slower, sustained release of the compound into the brain. In animal models, this new compound crossed the blood-brain barrier effectively and stimulated key serotonin receptors but produced significantly fewer “head twitches”—the gold-standard indicator for psychedelic activity in mice.
Key Facts
- Dissociating the “Trip”: The study confirms that the antidepressant/therapeutic effects of psychedelics can likely be separated from the hallucinogenic experience.
- The “4e” Candidate: Among five synthesized derivatives, compound 4e showed the best stability and absorption, providing a gradual release of psilocin rather than a sharp peak.
- Brain Penetration: 4e successfully crossed the blood-brain barrier and maintained a lower but more sustained presence in the brain compared to standard psilocybin.
- Reduced Behavioral Markers: Mice treated with 4e exhibited significantly fewer psychedelic-like behaviors (head twitches) while maintaining full activity at serotonin receptors.
- Broad Potential: This “non-trippy” version of the drug could eventually be used to treat not just depression and anxiety, but also neurodegenerative diseases like Alzheimer’s.
Source: ACS
Psilocybin — the psychoactive compound in “magic mushrooms” — is gaining scientific attention for its potential in treating neuropsychiatric conditions including depression, anxiety, substance use disorders and certain neurodegenerative diseases. However, its hallucinogenic effects may limit broader therapeutic applications.
Researchers publishing in ACS’ Journal of Medicinal Chemistry synthesized modified versions of psilocin, the active form of psilocybin, that retained their activity while producing fewer hallucinogenic-like effects than pharmaceutical-grade psilocybin in a preliminary study in mice.
“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.”
Mood disorders and some neurodegenerative diseases, such as Alzheimer’s disease, involve imbalances of the neurotransmitter molecule serotonin, which helps regulate mood and other brain functions.
For decades, scientists have been investigating the therapeutic use of psychedelics such as psilocybin on serotonin-signaling pathways. However, the hallucinations that can accompany these drugs may make people wary of taking them, even if there is a medical benefit.
So, a team led by Sara De Martin, Mattarei and Paolo Manfredi chemically engineered five psilocin derivatives for slower, sustained and potentially non-hallucinogenic release into the brain. They first tested these five compounds using human plasma samples and laboratory conditions mimicking gastrointestinal absorption.
These experiments allowed the team to identify a compound they named 4e as the most promising candidate because it displayed favorable stability for absorption and enabled a gradual release of psilocin — a feature that could potentially mitigate hallucinogenic effects. Importantly, 4e retained activity at key serotonin receptors at levels comparable to psilocin.
Next, the researchers compared the effects of equivalent doses of 4e with pharmaceutical-grade psilocybin in mice. The team administered the compounds orally to mice and measured how much psilocin reached the bloodstream and brain over a 48-hour period.
In mice dosed with 4e, the compound was able to cross the blood–brain barrier effectively and exhibited a lower but more sustained presence of psilocin in their brains compared to those treated with psilocybin.
When the researchers looked at mouse behavior, they observed that 4e-treated animals exhibited significantly fewer head twitches — a well-established marker of psychedelic-like activity in rodents — than those receiving psilocybin, despite the strong serotonin receptor activity of 4e.
This behavioral difference appeared to be associated primarily with 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 retain serotonin receptor activity while reducing acute mind-altering effects.
Further studies will be needed to clarify their mechanism of action and fully characterize their biological effects before assessing their therapeutic potential and safety in humans.
Funding: 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.
Key Questions Answered:
A: Recent science suggests the answer is yes. While some believe the “mystical experience” is necessary for healing, this study supports the idea that the brain-repairing effects (neuroplasticity) happen at the cellular level through serotonin receptors. By keeping those receptors active without flooding the brain all at once, you get the “repair” without the “hallucinations.”
A: Hallucinations are often triggered by a rapid spike of psilocin in the brain. The 4e compound acts like an “extended-release” version of the drug. It keeps the therapeutic levels steady and low, avoiding the threshold that triggers mind-altering effects while still providing the mood-regulating benefits.
A: We are still in the early stages. The results in mice are very promising, but the next steps involve full safety profiles and eventually human clinical trials to ensure that the “non-hallucinogenic” effect carries over from mice to people.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology research news
Author: Sarah Michaud
Source: ACS
Contact: Sarah Michaud – ACS
Image: The image is credited to Neuroscience News
Original Research: Open access.
“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. Journal of Medicinal Chemistry
DOI:10.1021/acs.jmedchem.5c01797
Abstract
Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N-Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure
Psilocybin, the phosphorylated prodrug of psilocin, holds therapeutic promise across a range of neuropsychiatric conditions, yet its clinical utility is constrained by acute psychoactive effects.
Here, we report the rational design, synthesis, and evaluation of a focused library of fluorinated reversible N-alkyl carbamate derivatives of psilocin aimed at reducing acute psilocin exposure and thereby limiting hallucinogenic-like effects. Carbamate bond stability was systematically modulated by varying the number and positioning of fluorine atoms on the alkyl promoiety.
The resulting compounds exhibited finely tuned hydrolysis under physiological conditions. A selected lead compound (4e) showed favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin.
Notably, 4e displayed intrinsic serotonergic activity at 5-HT2A and 5-HT2C receptors but induced attenuated psychotropic effects relative to psilocybin.
Overall, these findings highlight fluorinated carbamate chemistry as a versatile platform to control psilocin exposure and serotonergic signaling, rather than the development of a classical pharmacologically inert prodrug.
