Psilocybin’s effect on human brain synaptic plasticity

Classical serotonergic psychedelics such as psilocybin and LSD are being investigated as potential treatments for several neuropsychiatric conditions. These compounds agonise the serotonin 2A receptor (5-HT2A R) and produce dose-dependent acute alterations in perception, emotion and cognition. One- or two-dose administrations of psilocybin have been associated with persistent positive emotional effects in healthy volunteers and symptom improvements in people with major depressive disorder and other conditions. A leading mechanistic hypothesis is that psychedelics promote neuroplasticity; preclinical work has reported rapid structural and functional synaptic changes following 5-HT2A R stimulation, including dendritic growth and upregulation of presynaptic markers such as Synaptic Vesicle glycoprotein 2A (SV2A). Johansen and colleagues set out to test whether a single oral dose of psilocybin increases synaptic density in the human brain, operationalised as SV2A binding measured with [11C]UCB-J PET. The study focused on two regions implicated in higher-order cognition and mood regulation, the frontal cortex and the hippocampus, and examined whether session setting and subjective aspects of the psychedelic experience related to any observed changes. The investigation used a single-arm, open-label design with baseline and one-week follow-up imaging to probe persisting synaptic effects after one dosing session.

Fifteen healthy volunteers were enrolled after comprehensive somatic and psychiatric screening; the study was approved by Danish regulatory and ethics bodies and preregistered. The intervention was a single oral dose of psilocybin at 0.3 mg/kg. Sessions occurred either inside an MRI scanner (participants 1–5), where functional MRI paradigms were also acquired, or in a calm intervention room with a curated music playlist (participants 6–15). Trained psychological support staff were present during all sessions and medical staff were available. Imaging comprised structural MRI on a Siemens Magnetom Prisma 3T scanner and PET on an HRRT scanner with arterial blood sampling and a 120-minute acquisition to enable metabolite-corrected arterial input functions. Regional time–activity curves were extracted for the hippocampus and a frontal cortex composite (orbitofrontal, medial/inferior/superior frontal gyri, anterior cingulate, precentral gyrus). Kinetic modelling used a one-tissue compartment model (1TCM) to estimate total volume of distribution (VT) and SRTM2 to estimate non-displaceable binding potential (BPND) with centrum semiovale as the reference region; modelling was implemented in R. Primary statistical testing compared mean changes in [11C]UCB-J VT and BPND from baseline to one week using one-tailed paired t-tests for the frontal cortex and hippocampus, in line with the preregistered hypothesis that SV2A would increase after psilocybin. A group-sequential design included a planned interim analysis at 80% information (n = 12) with an adjusted significance threshold of 0.028 and a futility rule (conditional power < 50%). Exploratory analyses examined effects of session environment and associations between imaging changes and subjective measures. Acute subjective effects were quantified on the day of dosing with the 5D-ASC (including Oceanic Boundlessness, Dread of Ego-Dissolution, Visionary Restructuralization dimensions) and the MEQ30; persisting effects were assessed at three months with the Persisting Effects Questionnaire (PEQ). Because of small sample size and potential inflated type I error in latent variable models (LVMs), permutation tests (10,000 permutations) were used for p-values where appropriate. Linear mixed-effects models and LVMs were employed to probe environment effects and links between mystical-type experiences and SV2A changes.

Fifteen participants completed baseline procedures; imaging parameters (injected dose, mass, free fraction) were comparable between baseline and one-week follow-up. The psilocybin sessions were generally well tolerated; one participant experienced brief anxiety that responded to psychological support and no other intervention-related adverse events were reported. The preplanned interim analysis used data from 12 participants with complete arterial blood data and found no statistically significant increase in VT one week after psilocybin. For these 12, mean VT differences were 0.3 (SD 2.6) mL/cm3 in the frontal cortex (p one-sided = 0.29), corresponding to a 2.3% change, and 0.3 (SD 2.0) mL/cm3 in the hippocampus (p one-sided = 0.33), corresponding to a 3.0% change. Conditional power analysis indicated a 24% chance of achieving significance at completion using the originally hypothesised effect size and only 2% using the observed effect size; because conditional power fell below the preregistered futility threshold of 50% the study was stopped for futility. BPND estimates (available for all 15 participants) showed mean differences of -0.01 (SD 0.35) in the frontal cortex (p one-sided = 0.54; ~0.03% change) and 0.01 (SD 0.28) in the hippocampus (p one-sided = 0.44; ~1.01% change). Exploratory analyses revealed a marked influence of session environment on subjective experience and on imaging changes. Using an LVM, participants dosed in the MRI environment reported significantly lower mystical-type experiences (latent "Mysticality"; βMR = -28, pperm = 0.02) and significantly lower positive persisting effects at three months (βMR = -33, pperm = 0.01); negative persisting effects did not differ significantly (βMR = +99% log‑transformed, pperm = 0.29). A likelihood-ratio test comparing mixed models with and without session environment as an interaction term indicated an environment effect on ΔVT in the frontal cortex (p = 0.03) and a trend in the hippocampus (p = 0.09). The between-environment difference in ΔVT was 3.0 mL/cm3 (95% CI [0.4; 5.5]) for the frontal cortex and 1.9 mL/cm3 (95% CI [-0.3; 3.9]) for the hippocampus. Participants dosed in the intervention room showed VT increases from baseline to one week of 1.1 mL/cm3 (95% CI [-0.5; 2.7]) in the frontal cortex and 0.8 mL/cm3 (95% CI [-0.5; 2.1]) in the hippocampus, corresponding to approximately 5–6% increases. Associations between subjective measures and SV2A changes were nominal and not statistically significant at conventional thresholds: a mixed-effects model estimated a 0.5 mL/cm3 increase in frontal VT per 10-unit increase in mysticality (p = 0.16) and 0.3 mL/cm3 for the hippocampus (p = 0.28). The latent positive persisting-effects score was associated with β = +2.6 points per mL/cm3 in both regions (p > 0.37). The latent negative-effects score (log-transformed) showed a negative association of -21% per mL/cm3 (p = 0.05).

Johansen and colleagues report the first human in vivo test of whether a single psychoactive dose of psilocybin increases synaptic density as indexed by SV2A PET. The primary analysis did not find a statistically significant overall increase in cerebral SV2A one week after dosing. However, setting had a substantial effect: participants dosed in a calm intervention room with curated music exhibited approximately 5–6% increases in SV2A binding in the frontal cortex and hippocampus, consistent with the study’s target effect size, whereas those dosed in the MRI environment did not. Subjective data mirrored this pattern; mystical-type experiences and positive persisting effects at three months were lower for participants dosed inside the scanner. The investigators suggest the results are compatible with a model in which synaptic plasticity after psilocybin is modulated by the psychological quality and emotional valence of the acute experience. They note that prior research has linked mystical-type experiences during psychedelic sessions to longer-term positive outcomes and that some mediation analyses from earlier clinical work support mystical experiences as partial drivers of therapeutic effects. The authors caution that healthy volunteers may exhibit smaller plasticity effects than clinical populations because of homeostatic mechanisms, and they highlight that patients with major depressive disorder tend to show lower baseline SV2A, so clinical samples might demonstrate larger upregulation post‑intervention. Timing of imaging is discussed as a key uncertainty: although preclinical data and a pig study motivated the choice of a one-week follow-up, the time course of synaptic remodelling in humans could differ, with possible transient increases at earlier time points that stabilise or are pruned by one week. Comparisons are drawn to other human PET studies (for example, ketamine studies showing no change at 24 hours) and to pharmacological challenges that have been associated with time-dependent SV2A alterations (escitalopram, cocaine). Methodological limitations are acknowledged: the absence of a placebo arm and reports from other SV2A studies of lower VT on the second scan could mean the paired design underestimated an increase; the group-sequential design used a stricter significance threshold for the primary analysis; exploratory analyses were not adjusted by prespecified multiplicity rules; and uncertainty in LVM-weighted scores was not incorporated, which may underestimate p-values. Finally, the authors emphasise implications for future research and practice: the session environment and psychological support (including music and therapeutic rapport) deserve systematic study and optimisation, and confirmatory trials in larger samples and clinical populations are needed to test the hypothesised links between subjective experience, synaptic plasticity and therapeutic outcomes.

The extracted Conclusion text is incomplete. The available fragment states that the study represents an important step towards understanding persisting effects of psilocybin on the human brain and indicates that the psychedelic experience is shaped by the session environment. The full concluding remarks are not present in the extracted text.