Setting may shape psilocybin’s effects on the brain, preliminary study suggests

A single dose of psilocybin did not produce a statistically significant overall increase in a brain marker of synapses in healthy adults one week later, according to a small study published in Translational Psychiatry. However, participants who took psilocybin in a calm room with music, rather than inside an MRI scanner, reported more intense mystical-type experiences and showed larger changes in the marker.

Synapses are the connection points that allow nerve cells to communicate. The brain can change these connections through a process known as synaptic plasticity, which is important for learning and adaptation. Researchers have proposed that changes in plasticity may help explain why some people report lasting mood effects after psychedelic experiences. But measuring synapses in the living human brain is difficult.

Annette Johansen of Copenhagen University Hospital and colleagues tested whether a single dose of psilocybin would increase synaptic density in the human brain. They used positron emission tomography (PET) imaging to measure SV2A, a protein found in synapses that serves as an indirect marker of synaptic density. The researchers’ earlier work had found higher SV2A levels in the brains of pigs one week after a single dose of psilocybin.

The study included 15 healthy adults (median age 32.5 years; 5 women), each of whom received a single oral dose of psilocybin chosen to reliably produce an intense psychedelic experience. The first five participants took psilocybin while lying in an MRI scanner and completing brain imaging tasks, while the remaining ten had their session in a dedicated room while listening to a curated music playlist. Two facilitators provided psychological support in both settings.

PET scans measured SV2A in the frontal cortex and hippocampus before dosing and again one week afterward. Participants also reported their experiences after the session and completed a questionnaire about persisting effects three months later.

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Across the whole group, the researchers did not find a statistically significant rise in SV2A. The average changes were small, around 2% to 3%, and the study stopped early after a planned interim analysis indicated it was unlikely to reach its target result. The primary finding therefore does not show that psilocybin increased the measured synaptic marker.

In further exploratory analyses, participants in the intervention room reported more intense mystical-type experiences and more positive lasting effects at three months than those dosed in the scanner. Negative lasting effects did not differ between the groups.

The two groups also differed in how their SV2A levels changed. The intervention-room group showed an average increase of about 5% to 6% in the frontal cortex and hippocampus, while the scanner group did not show an increase. The difference between the groups was statistically significant in the frontal cortex but not in the hippocampus, and the increase within the intervention-room group was not statistically significant on its own. More intense mystical-type experiences were associated with larger SV2A increases, but this association was also not statistically significant.

The authors concluded: “these findings indicate that psilocybin’s neuroplastic effects are modulated by environmental context, with important implications for psychedelic-assisted therapies.” Elsewhere in the paper, however, they describe the differences in SV2A between settings as “preliminary and hypothesis-generating rather than conclusive,” given the small sample. The researchers suggest that a supportive environment may promote positive emotional experiences and a sense of safety that could facilitate changes in brain connections, while a stressful or distracting setting such as an MRI scanner may limit them.

The findings have substantial caveats. There was no placebo group, and participants were not randomly assigned to the two settings; the five scanner participants were simply the first five enrolled. The scanner group was very small, and the two settings differed in many ways at once, including the noise and confinement of the scanner, the imaging tasks, and the music.

The study also included healthy adults rather than people receiving psilocybin as a treatment, and the authors note that effects might be larger in people with depression, who tend to have lower SV2A levels. Previous studies have found that SV2A measurements tend to be lower on a second scan, which could mean the study underestimated any increase. One author’s salary was supported by COMPASS Pathways, a company developing psilocybin therapy, and two other authors have ties to companies developing psychedelic drugs.

The study, “Psilocybin’s effect on human brain synaptic plasticity,” was authored by Annette Johansen, Pontus Plavén-Sigray, Martin K. Madsen, Anna Søndergaard, Catharina Messel, Maria Geisler, Arafat Nasser, Drummond E-W. McCulloch, Vincent Beliveau, Alexandra Vassilieva, Anton Lund, Szabolcs Lehel, Brice Ozenne, Dea S. Stenbæk, Patrick M. Fisher, Claus Svarer and Gitte M. Knudsen.