This pre-print double-blind placebo-controlled trial (n=15) found that healthy participants who had a psilocybin-induced psychedelic experience in a therapeutic-like room exhibited more intense mystical-type experiences, longer-lasting psychological benefits, and greater increases in synaptic density than those dosed inside an MRI scanner, indicating that psilocybin’s neuroplastic effects are modulated by environmental context.
Abstract of Psilocybin’s effect on human brain synaptic plasticity
“Psychedelics such as psilocybin have been linked to enhanced neuroplasticity and symptom relief in affective disorders, but the neurobiological mechanisms and impact of environmental context remain unclear. Here, we tested whether a single dose of psilocybin alters synaptic density in healthy individuals and whether setting-dependent subjective experience shapes this effect. Fifteen healthy participants had a psilocybin-induced psychedelic experience either inside an MRI scanner or in a therapeutic-like room. We assessed synaptic density changes by measuring the Synaptic Vesicle glycoprotein 2A in the frontal cortex and hippocampus with [¹¹C]UCB-J PET at baseline and one week post-dose, and assessed subjective experiences immediately afterwards and at three months. Participants treated in the therapeutic-like setting exhibited more intense mystical-type experiences, longer-lasting psychological benefits, and greater increases in synaptic density than those dosed in the MRI scanner. These findings indicate that psilocybin’s neuroplastic effects are modulated by environmental context, with important implications for psychedelic-assisted therapies.”
Authors: 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 & Gitte M. Knudsen
Summary of Psilocybin’s effect on human brain synaptic plasticity
This preprint investigates whether psilocybin induces measurable synaptic plasticity in the healthy human brain and whether the immediate environment in which dosing occurs modulates that biological signal and the subjective experience. Psilocybin is a classic psychedelic acting primarily as an agonist at the serotonin 2A receptor (5-HT2A). Activation of this receptor is known to acutely alter perception, emotion and cognition, and earlier research has linked one or two administrations of psilocybin to long-lasting psychological benefits and clinical improvement across several disorders. The central mechanistic hypothesis tested here is that psilocybin increases synaptic density—an index of structural neuroplasticity—detectable in vivo using positron emission tomography (PET) with the SV2A (Synaptic Vesicle glycoprotein 2A) radiotracer [¹¹C]UCB-J. All details below are taken directly from Johansen and colleagues’ preprint, “Psilocybin’s effect on human brain synaptic plasticity.”
To anchor the outcome measure, the authors focus on SV2A because it is expressed ubiquitously in presynaptic terminals and is considered a reliable proxy for synaptic density in living human brain tissue. They also target two regions of a priori interest—the frontal cortex and hippocampus—given convergent evidence from animal work showing post-psilocybin increases in presynaptic markers there and the involvement of these regions in high-level cognition, memory and affect regulation. A second, closely linked question examines “set and setting”: if the dosing environment shapes acute mystical-type experiences and long-term psychological benefits, does it also shape the biological plasticity signal?
Methods
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Psilocybin’s effect on human brain synaptic plasticity
https://doi.org/10.21203/rs.3.rs-7469144/v1
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Cite this paper (APA)
Knudsen, G., Johansen, A., Plavén-Sigray, P., Madsen, M., Søndergaard, A., Messel, C., ... & Svarer, C. (2025). Psilocybin’s effect on human brain synaptic plasticity.
Study details
Compounds studied
Psilocybin
Topics studied
Neuroscience
Study characteristics
Original
Open-Label
Participants
15
Humans
Compound Details
The psychedelics given at which dose and how many times
Psilocybin 21 mg | 1xLinked Research Papers
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