A small study suggests the brain’s response to psilocybin may depend on the context in which the session occurs, rather than there being a universal increase in a key synaptic marker. In healthy adults, a single dose did not produce a statistically significant overall rise in SV2A, a PET-detectable protein linked to synapses, one week after dosing. Yet participants who took psilocybin in a calm room with a curated music playlist reported more intense mystical-type experiences and showed larger changes in the marker.
The research was led by Annette Johansen of Copenhagen University Hospital and colleagues, and used positron emission tomography to measure SV2A as an indirect marker of synaptic density. Earlier work in pigs had found higher SV2A levels a week after a single psilocybin dose, prompting the investigators to test whether a similar effect might appear in humans.
Fifteen healthy adults participated, with a median age of 32.5 years and five women in the group. Each received a single oral dose of psilocybin intended to reliably produce a vivid psychedelic experience. The first five participants were dosed while lying in an MRI scanner undergoing brain imaging tasks, while the remaining ten sessions occurred 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.
Across the full sample, researchers did not find a statistically significant rise in SV2A. The average changes were small, around 2% to 3%, and the study was terminated early after an interim analysis indicated it was unlikely to achieve its target result. The primary finding therefore does not show that psilocybin increased the measured synaptic marker.
In exploratory analyses, participants dosed 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 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 settings 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 tended to be associated with larger SV2A increases, but this association was not statistically significant.
“these findings indicate that psilocybin’s neuroplastic effects are modulated by environmental context, with important implications for psychedelic-assisted therapies,” the authors concluded. 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 study carries substantial caveats. There was no placebo group, and participants were not randomised 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.
Participants were healthy adults rather than individuals receiving psilocybin as 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,” lists Annette Johansen as lead author, with 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 among the contributors.
