Modified psilocin compound keeps serotonin activity but loses the hallucinations -- in mice

The therapeutic promise of psilocybin has a practical problem attached to it. The compound, found in "magic mushrooms," has shown potential in clinical trials for depression, anxiety, substance use disorders, and certain neurodegenerative conditions. But it also makes people hallucinate. For a drug that might need to be taken repeatedly, or prescribed to elderly patients with cognitive decline, the hallucinogenic effects are not just a side effect -- they are a barrier to adoption.

A team of researchers led by Sara De Martin, Andrea Mattarei, and Paolo Manfredi has now published work in the Journal of Medicinal Chemistry showing that the hallucinations and the therapeutic activity may not be inseparable. They engineered modified versions of psilocin -- the active metabolite that psilocybin converts to in the body -- and found at least one candidate that retains the serotonin receptor activity while producing significantly fewer hallucinogenic-like effects. In mice, anyway.

The logic of slow release

Psilocybin's hallucinogenic effects are thought to relate, at least in part, to the pharmacokinetic profile of psilocin in the brain. After oral administration, psilocybin is rapidly converted to psilocin, which hits serotonin receptors -- particularly the 5-HT2A receptor -- in a sharp spike. The hypothesis driving this work is that a slower, more sustained release of psilocin might activate the same receptors at therapeutically relevant levels without producing the intense perceptual distortions associated with a rapid peak.

The team synthesized five psilocin derivatives designed to be absorbed through the gastrointestinal tract and then release psilocin gradually. They screened these compounds using human plasma samples and lab conditions that mimic GI absorption, looking for stability and release kinetics.

Compound 4e

One derivative, designated 4e, emerged as the most promising candidate. It showed favorable stability for absorption and enabled a gradual, sustained release of psilocin rather than the sharp spike produced by psilocybin. Critically, 4e retained activity at key serotonin receptors at levels comparable to psilocin itself.

When the researchers moved to mouse experiments, they compared equivalent doses of 4e and pharmaceutical-grade psilocybin. Both were administered orally, and psilocin levels in the bloodstream and brain were measured over 48 hours.

In mice dosed with 4e, psilocin reached the brain effectively -- the compound crossed the blood-brain barrier without difficulty. But the brain concentration profile was different: a lower peak with a longer duration, compared to the sharp spike-and-fall pattern seen with psilocybin.

The behavioral test was the head-twitch response, a well-established marker of psychedelic-like activity in rodents. Mice receiving 4e showed significantly fewer head twitches than those receiving psilocybin, despite 4e's strong serotonin receptor engagement. The difference appeared to be driven primarily by the amount and timing of psilocin released in the brain.

Dissociating the trip from the treatment

"Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic activity may be dissociated," said Mattarei. "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."

If that dissociation holds up in further testing, the implications are considerable. Current psilocybin therapy typically requires supervised sessions lasting several hours, partly because of the intensity of the hallucinogenic experience. A non-hallucinogenic version could potentially be prescribed more like a conventional antidepressant -- taken at home, without the need for clinical supervision during each dose.

Mouse model, human questions

The standard caveats apply here, and they are substantial. The head-twitch response in mice is an imperfect proxy for human hallucinatory experience. A mouse cannot report whether it is seeing patterns or experiencing ego dissolution. The correlation between head twitches and human psychedelic effects is well-established but not absolute.

More fundamentally, there is an active debate in psychedelic research about whether the hallucinogenic experience itself contributes to therapeutic outcomes. Some clinical researchers argue that the subjective "mystical experience" induced by psilocybin is integral to its antidepressant effects. If that is the case, removing the hallucinations might also remove part of the therapeutic benefit. This study does not address that question directly.

The researchers acknowledge that further studies will be needed to clarify the mechanism of action and fully characterize the biological effects of 4e before assessing its therapeutic potential and safety in humans. Several authors are inventors on patents related to psilocin, and the work was funded by MGGM Therapeutics, LLC, in collaboration with NeuroArbor Therapeutics Inc.