First human trial of psilocin since the 1960s reveals better tolerability than psilocybin

Recent research suggests that consuming psilocin, the active compound in “magic” mushrooms, might cause fewer side effects than taking psilocybin. The study also explored taking the drug under the tongue, finding it well tolerated though less intense at the tested doses. The findings were published in Journal of Psychopharmacology.

Psilocybin is a naturally occurring compound found in certain hallucinogenic mushrooms. In recent years, it has gained attention as a potential treatment for mental health conditions. For example, a study covered by PsyPost in 2021 noted that psilocybin therapy could offer symptom relief comparable to some conventional antidepressants.

However, psilocybin itself does not directly cause psychedelic effects. It is a prodrug, meaning the body must break it down to activate it. When a person swallows psilocybin, enzymes in the gut and liver strip away a phosphate molecule, converting it into a new chemical called psilocin.

Psilocin is the active substance that enters the brain and alters perception. In fact, a 2019 study indicated that the intensity of a person’s psychedelic experience closely matches the concentration of psilocin circulating in their blood. Because the body’s conversion process can vary from person to person, standard oral psilocybin often yields unpredictable results and tends to cause unpleasant side effects.

“Nearly every modern psilocybin trial has used the same thing: synthetic psilocybin, 25 mg, in a capsule,” Josh Woolley, an associate professor of psychiatry at the University of California, San Francisco and director of the Translational Psychedelic Research Program, told PsyPost. “There are reasons to think other options might work better. Psilocybin is a prodrug, so the body has to convert it to psilocin, and people vary a lot in how efficiently they do that. That may be part of why responses to a fixed dose are so variable.”

Free daily newsletter

Researchers wanted to know if administering psilocin directly would skip this metabolic step, potentially offering a gentler and more predictable experience. They also wanted to test a sublingual route, which involves placing a dissolving tablet under the tongue. Sublingual administration allows a drug to absorb directly into the bloodstream through the tissues of the mouth, completely bypassing the digestive system.

“Nobody had given psilocin directly to a human since the 1960s, and nobody had tried a sublingual formulation of any of these compounds,” Woolley noted.

Additionally, the research team used botanical extracts rather than lab-made synthetic chemicals. These whole-mushroom formulations contain natural trace compounds, known as alkaloids, alongside the primary drug. Alkaloids are naturally occurring chemical compounds found in plants and fungi that produce physiological effects on the body, and some researchers suspect they might influence the overall experience. “Mushrooms contain other alkaloids besides psilocybin, and standardized botanical extracts now make it possible to test whole-mushroom formulations under pharmaceutical conditions, which hadn’t been done,” Woolley said.

The research, led by Marlene L. Tai and Woolley, aimed to compare these different methods in a controlled setting. The scientists recruited 20 healthy adults between the ages of 25 and 50. All participants had prior experience with psychedelics and reported mild feelings of social disconnection. The study used a crossover design, meaning each person received multiple different treatments on separate days to compare the effects within the same individual.

Participants attended up to four drug administration sessions spaced four weeks apart. During these sessions, they received either an oral capsule of psilocybin (25 milligrams), an oral capsule of psilocin (17.5 milligrams, a dose designed to match the psilocybin strength), or a sublingual tablet of psilocin. The initial sublingual dose was set low at 2.18 milligrams and later increased to 4.36 milligrams or 8 milligrams to assess safety and tolerability.

All sessions took place in a comfortable clinic room where participants wore eyeshades and listened to music. A therapist and an assistant stayed in the room to provide psychological support. Throughout the day, the research team measured blood pressure and heart rate, while participants rated the intensity of the drug’s effects every 15 to 30 minutes.

At the end of each session, participants completed several questionnaires. These surveys measured the emotional and psychological qualities of their experience, including feelings of unity, emotional breakthroughs, and challenging states like fear or paranoia.

When comparing the two oral capsules, the scientists found that psilocin produced a psychological and physical journey that was very similar to psilocybin. The onset time, peak intensity, and duration of the experiences were mostly indistinguishable. Both drugs reliably produced deep psychological insights and mystical-type experiences.

“We expected psilocin to come on faster, since it skips a metabolic step, and it didn’t,” Woolley explained. “The two were hard to tell apart on almost every measure.”

However, oral psilocin was associated with a lower overall burden of adverse side effects. While almost all participants experienced mild issues on both drugs, oral psilocybin was linked to more moderate and severe events. These included headaches, anxiety, and one instance of transient loss of consciousness. Interestingly, gastrointestinal issues like nausea were similar between the two oral drugs, suggesting that stomach upset is not solely caused by the body breaking down psilocybin.

“The tolerability difference was modest, not dramatic,” Woolley said. “Fewer and milder adverse events on average, mostly headache and anxiety, rather than a categorical improvement. Whether that matters clinically depends on the setting. In a treatment where one session already requires eight hours of monitoring, small reductions in burden can add up. But this was 18 people per condition, so it’s a signal worth following, not an established difference.”

The sublingual psilocin tablets proved safe and were well tolerated by the participants. But the physical and psychological effects were much milder than the oral doses. The subjective intensity and cardiovascular responses were noticeably lower, indicating that less of the drug made its way into the systemic circulation at the tested amounts.

“At the cautious doses we used with FDA input, we clearly didn’t reach the exposure needed to test whether the route has real advantages,” Woolley noted. “This is an early study in 20 healthy volunteers. It’s a first look, not a verdict.”

Despite the milder overall intensity, sublingual psilocin still facilitated notable psychological responses. Participants reported scores on measures of emotional breakthrough and psychological insight that rivaled those typically seen with much higher oral doses. The authors noted that this suggests even mild psychedelic exposures might offer some therapeutic benefit.

“One result we’re still thinking about,” the researcher stated. “Even the very mild sublingual doses produced emotional breakthrough scores comparable to the full 25 mg doses. That could be a false positive, or an effect of the psychotherapy rather than the drug. But if it holds, it raises a real question about whether an intense psychedelic experience is necessary for the psychological benefits people are after.”

In an exploratory analysis, the researchers also compared their botanical mushroom extracts to data from a separate trial that used synthetic psilocybin. The psychological effects were broadly similar. This provides evidence that standardized whole-mushroom extracts function much like lab-made versions, offering a viable alternative for future treatments.

“On the botanical question, our comparison was with data from a previously published trial of synthetic psilocybin, not with a synthetic arm in our own study,” Woolley explained. “Two different populations, two different settings. So the fair statement is that we saw nothing that would suggest a big difference, not that we ruled one out. Testing the ‘entourage effect’ properly would require a head-to-head comparison in the same trial.” This entourage effect is the theory that multiple natural compounds within a plant or mushroom work together synergistically to produce stronger or different effects than an isolated chemical alone.

As with all research, there are a few things to keep in mind. The study included a small group of healthy, highly educated volunteers who already had experience with psychedelics. Because of this, it is not guaranteed that people with severe mental health conditions or those entirely new to psychedelics would respond in the exact same way.

The researchers also emphasized the strict clinical environment used during the trial. “The main one is that nothing here suggests people should be taking mushroom extracts on their own or trying to convert psilocybin to psilocin at home,” Woolley warned. “These were pharmaceutical grade products made to Good Manufacturing Practice standards, given under continuous medical supervision with a licensed therapist present throughout. That matters. One participant briefly lost consciousness during a psilocybin session, which we’ve reported separately, and it was handled because clinicians were in the room.”

The trial also lacked a pure inactive placebo group. Because the sublingual doses produced noticeably milder physical sensations than the oral capsules, participants and therapists were often able to guess which treatment had been administered. This awareness could have influenced the subjective survey responses.

Finally, the research team did not collect blood samples during the sessions. Without measuring the actual concentration of psilocin in the blood, it is difficult to know exactly how much of the sublingual drug was absorbed or how individual metabolisms processed the oral capsules. Future studies will need to incorporate blood testing and try higher sublingual doses to fully evaluate this delivery method.

“Measuring actual psilocin levels is what would let us link formulation to exposure to effect, and its absence was our main limitation here,” Woolley observed. “Sublingual psilocin needs a proper dose-ranging study at higher doses. And eventually this has to be tested in people with the conditions these drugs might treat, not just healthy volunteers.”

Moving forward, the team intends to share additional findings from the current participants. “We have a companion paper in preparation from this same trial looking at longer-term psychological outcomes, including loneliness, out to six months,” Woolley, who also serves as a staff psychiatrist at the San Francisco VA Medical Center, added. “That’s the other half of the story and we’ll have more to say when it’s out.”

The study, “A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin,” was authored by Marlene L. Tai, Balázs Szigeti, Amanda E. Downey, Jacob S. Aday, Lisa Fredenburg, Kimberly Sakai, Cesar Molina, Gisele Fernandes-Osterhold, Ellen R. Bradley, Maddie Pantoni, Ryan Moss, Benjamin Lightburn, Franziska Plessow, Aoife O’Donovan, and Josh D. Woolley.