A single psilocybin dose increased frontal and hippocampal synaptic density in healthy participants one week after dosing, measured with [11C]UCB-J PET targeting synaptic vesicle glycoprotein 2A (SV2A). Participants dosed in a therapeutic-like room showed stronger mystical-type experiences, longer-lasting psychological benefits and greater synaptic increases than those dosed inside an MRI scanner, indicating that psilocybin’s neuroplastic effects are modulated by environmental context.
Psychedelics such as psilocybin have been linked to enhanced neuroplasticity and symptom relief in affective disorders, but the neurobiological mechanisms and impact of environmen-tal context remain unclear. Here, we tested whether a single dose of psilocybin alters synap-tic density in healthy individuals and whether setting-dependent subjective experience shapes this effect. Fifteen healthy participants had a psilocybin-induced psychedelic experi-ence either inside an MRI scanner or in a therapeutic-like room. We assessed synaptic densi-ty changes by measuring the Synaptic Vesicle glycoprotein 2A in the frontal cortex and hip-pocampus 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 thera-peutic-like setting exhibited more intense mystical-type experiences, longer-lasting psycho-logical benefits, and greater increases in synaptic density than those dosed in the MRI scan-ner. These findings indicate that psilocybin’s neuroplastic effects are modulated by envi-ronmental context, with important implications for psychedelic-assisted therapies.
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.
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Vollenweider, F. X., Preller, K. H. · Nature Reviews Neuroscience (2020)
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.
Classical psychedelics such as psilocybin and lysergic acid diethylamide (LSD) are emerging as potential therapeutics for treating a range of neuropsychiatric disorders. The compounds stimulate the serotonin 2A receptor (5-HT 2A R), which acutely induces a dose-dependent altered state of consciousness including perceptual, emotional, and cognitive changes. Intake of only one to two doses of psilocybin is associated with long-lasting positive emotional effects in healthy individuals (4, 5) and symptom improvement in patients with major depressive disorder (MDD) (6-8), anxiety, addictionand cluster headache. A compelling hypothesis for the rapid therapeutic action of psychedelics is their ability to induce neuroplasticity. The psychological plasticity which manifests through increased cognitive exibility and psychological insighthas been suggested to be linked to functional and microstructural changes in the brain, a view that has been bolstered by a growing body of preclinical studies (18-21). The neuroplastic effects of psychedelics are coupled to activation of the 5-HT 2A R; when cultured neurons are stimulated with 5-HT 2A R agonists, structural and functional changes such as dendritic sprouting and arborization and upregulation of presynaptic markers emerge. This happens as early as six hours after 5-HT 2A R stimulation, with persisting effects detected up to seven days later. One week after awake pigs are given a single dose of i.v. psilocybin, they display higher density of the presynaptic marker, Synaptic Vesicle glycoprotein 2A (SV2A), in the hippocampus and frontal cortex, as compared to saline-treated animals. SV2A can be quanti ed in vivo in the human brain using positron emission tomography (PET) with the tracer [ 11 C]UCB-J (26). In the human cerebral cortex, SV2A is highly expressed with a regional distribution re ecting higher-order human brain functions. Results from our previous study suggest that 3-5 weeks of intake of the selective serotonin reuptake inhibitor, escitalopram, is associated with higher SV2A levels in a time-dependent manner, supporting that the delay in therapeutic action is associated with an increased synaptic density, putatively re ecting structural plasticity (28). In contrast, the positive psychological effects of psilocybin occur immediately following the dosing session and persist long after the drug has been cleared from the body. Positive emotional experiences during the session, as captured by the Mystical Experience Questionnaireand the Oceanic Boundlessness facet of the Altered State of Consciousness Questionnaire )have been linked to better therapeutic outcomes in patientsand lasting positive effects in healthy individuals. A central question is how aspects pertaining to the psychedelic experience relate to neuroplasticity and lasting positive effects. In a single-arm, open-label study, we investigated whether a single psychedelic dose of psilocybin increases cerebral SV2A levels-as measured with [¹¹C]UCB-J PET -in healthy individuals, by estimating SV2A density in the frontal cortex and the hippocampus before and one week after the session. We explore how changes in SV2A density relate to the settings of the psilocybin session and subjective effects during the psychedelic experience.
Fifteen healthy volunteers were recruited from a local database of individuals who had expressed interest in participating in studies involving psilocybin. Following informed consent, participants underwent extensive screening procedures including somatic and psychiatric medical history, clinical examination, standard blood biochemistry, and an electrocardiogram to exclude the presence of prior or current major somatic or psychiatric disorder. The study was approved by the Danish Medicines Agency (EudraCT ID: 2016-004000-61, amendments: 2020061833, 2021041519) and by the ethics committee for the Capital Region of Denmark (ID: H-16028698, with amendments). The study was preregistered at ClinicalTrials.gov (NCT03289949, subproject 2b).
The study was designed as an open label, group-sequential single arm intervention study. A single interim analysis was planned at 80% of the recruitment (n = 12 individuals with complete data), with the possibility to stop the study for e cacy, or futility, or continue recruitment until n = 15 individuals with complete data. Participants underwent Magnetic Resonance Imaging (MRI) and [ 11 C]UCB-J PET scans approximately one week before undergoing an intervention session with peroral psilocybin (0.3 mg/kg). The psilocybin sessions took place in either an MRI scanner with a series of functional MRI acquisitions including active and passive paradigms (participants 1-5), or in a designated intervention room while listening to a curated music playlist constructed to facilitate the different phases of the psychedelic experience(participants 6-15). In both environments, trained psychological support staff was present throughout the intervention day to provide interpersonal support, and medical staff were on site to react to potential adverse events. One week after the psilocybin session, participants returned for follow-up [ 11 C]UCB-J PET and MRI scans. iii. Subjective effects questionnaires Psychological questionnaires evaluating the acute effects of psilocybin were completed on the day of the psilocybin session, after psychedelic effects had subsided, and included the Altered State of Consciousness Questionnaire (5D-ASC, scale 0-100)and the Revised Mystical Experience Questionnaire-30 (MEQ30, scale 0-5). From the 5D-ASC questionnaire, 11 subscales were created from the dimensions Oceanic Boundlessness (OBN) which assesses "mystical-type experiences" (comprising the subscales Experience of unity, Blissful state, Spiritual experience, Insightfulness, and Disembodiment); Dread of Ego-Dissolution (DED) which is concerned with negative experiences and anxiety (comprising the subscales Anxiety and Impaired control and cognition); and Visionary Restructuralization (VRS) assessing effects on sensory perception (comprising the subscales Complex imagery, Elementary imagery, Audio-visual synesthesia, Changed meanings of percepts). The MEQ30 shares features with the OBN dimension of the ASC and contains the subscales Mystical, Positive mood, Transcendence of time and space, and Ineffability. Persisting effects were evaluated three months after the psilocybin session using the Persisting Effects Questionnaire (PEQ) (36), which assesses positive and negative effects on life, self, mood, behavior, social effects, and spirituality attributed to the psychedelic experience. iv. Imaging acquisition and processing MRI data were acquired on a Siemens Magnetom Prisma 3T scanner using a 32-channel head coil (Siemens AG, Erlangen, Germany). PET data were acquired over 120 min with the high-resolution research tomograph (HRRT) PET scanner (CTI/Siemens, Knoxville, TN, USA) with collection of arterial blood samples to establish a metabolite-corrected arterial input function. Details on MRI and PET parameters and processing are provided in the supplementary le. v. Kinetic modeling of PET and blood data Kinetic modeling of [ 11 C]UCB-J PET data was performed in R (v. 4.2.2, R Foundation, Vienna, Austria) using the kin tr packagev. 0.6(37). Regional time-activity curves from the hippocampus and frontal cortex (volume-weighted average of orbitofrontal cortex, medial and inferior frontal gyrus, superior frontal gyrus, anterior cingulate gyrus, precentral gyrus) and the corresponding metabolite-corrected arterial input function were tted to the one-tissue compartment model (1TCM) to estimate the total volume of distribution (V T ). As an alternative outcome parameter, the time-activity curves were tted using the simpli ed reference tissue model 2 (SRTM2) to estimate the non-displaceable binding potential (BP ND ) using the white matter region centrum semiovale as the reference region, and the median k2 from 1TC modeling of centrum semiovale as a global k2' as determined within the sample.
For the primary analysis, mean changes in [ 11 C]UCB-J V T and BP ND between baseline and one week follow-up were assessed using one-tailed paired t-tests for the frontal cortex and the hippocampus to test the hypothesis that SV2A binding increase after psilocybin intervention in accordance with the preregistration protocol (aspredicted.org ID: 93092, see supplementary material). We also pre-registered an interim test at n = 12/15 (information fraction = 0.8) with an adjusted signi cance level of 0.028, allowing us to stop for e cacy or futility (conditional power < 50%). Tests with one-sided p-values are referred to as p one-sided . In exploratory analyses, we investigated 1) whether the self-reported MEQ30 and 5D-ASC scores rated immediately after the intervention and PEQ rated three months after the intervention differed between session environments, 2) whether change in SV2A binding differed between session environments, and 3) whether change in SV2A binding was associated with the subjective intensity of mystical-type experiences and persisting effects. For these analyses, we applied a linear latent variable model (see Figurefor graphical representation) (38) with a latent variable, Mysticality, to capture the shared correlation between the ASC subscales Experience of Unity, Spiritual Experience, Blissful State, Insightfulness, and Disembodiment combined with the MEQ sub-scales (rescaled to 0-100) Mystical, Positive Mood, Transcendence of Time and Space, and Ineffability. For the persisting effects, we applied latent variable models with the latent variables Positive Persisting Effect and Negative Persisting Effects, to capture the shared correlation between the positive and negative PEQ subscales, respectively (see Figurefor graphical representation). A separate parameter was used in each model to estimate the mean latent variable scores in the MRI scanner and intervention room. Because standard LVM tests exhibit in ated type 1 error in small samples (39), permutation tests with 10,000 permutations were performed to compute the p-values (referred to as p perm ). For the [ 11 C]UCB-J V T s we compared a random-intercept linear mixed-effects model including the session environment as an interaction term to a model without the session environment using a likelihood ratio test (for the frontal cortex and the hippocampus separately). We next examined the association between the mysticality latent variable scores and the [ 11 C]UCB-J V T s.
Participant demographics and summary statistics of [ 11 C]UCB-J PET scan parameters are presented in Table. Injected dose, weight-adjusted injected mass, and free fraction of [ 11 C]UCB-J were comparable between baseline and the one-week follow-up. Psilocybin interventions were generally well-tolerated in both session environments. One participant in the intervention room brie y experienced anxiety as the drug's effects emerged but responded well to psychological support. No other participants experienced adverse effects related to the intervention.
The interim analysis, based on 12 participants with complete arterial blood data, showed no statistically signi cant increase in V T following the psilocybin intervention. The conditional power analysis indicated 24% probability of reaching signi cance at study completion with the originally hypothesized effect size, and 2% probability with the observed effect size. As this fell below our pre-registered futility threshold of 50% conditional power, the study was terminated for futility. For these 12 participants, the mean difference (SD) in V T was 0.3 (2.6) mL/cm 3 (p one-sided = 0.29) corresponding to 2.3% in the frontal cortex, and 0.3 (2.0) mL/cm 3 (p one-sided = 0.33) corresponding to 3.0% in the hippocampus (Figure). BP ND s calculated for all 15 participants showed a mean difference (SD) of -0.01 (0.35) (p one-sided = 0.54) corresponding to 0.03% in the frontal cortex, and 0.01 (0.28) (p one- sided = 0.44) corresponding to 1.01% in the hippocampus (Figure).
We examined whether the session environments were associated with differences in participants' subjective mystical-type experiences during the psilocybin session and their persisting effects three months after the session. Using an LVM (Figure), we found that participants who underwent the psilocybin session in the MR environment reported signi cantly lower intensity of mysticality (β MR = -28, p perm = 0.02). The ASC-OBN subscales showed similar contribution to the latent variable with loadings close to 1 and highly signi cant p-values, except for Disembodiment. The MEQ subscales Transcendence of time and space and Ineffability also showed low loading weights (0.59 for both), whereas the other loadings were close to 1. The distribution of individual subscale raw scores is shown in Figure. Similarly, the participants who underwent the psilocybin session in the MR environment reported signi cantly lower positive persisting effects (β MR = -33, p perm. = 0.01, Figure), while negative persisting effects did not differ signi cantly (β MR = +99% (log-transformed), p perm. = 0.29, Figure). Given the signi cant differences in both intensity of mystical-type experiences and positive persisting effects between the participants in the intervention room and those in the MR scanner, we examined whether SV2A binding changes (ΔV T s) differed between the subgroups. A likelihood ratio test comparing a model with and without the session environment variable as an interaction term showed an effect of the session environment on ΔV T s for the frontal cortex (p = 0.03) and the hippocampus (p = 0.09). The difference in ΔV T between the two session environments was 3.0 mL/cm 3 (95% CI [0.4;5.5]) in the frontal cortex and 1.9 mL/cm 3 (95% CI [-0.3;3.9) in the hippocampus. For participants in the intervention room, V T s increased from baseline to 1-week follow-up by 1.1 mL/cm 3 (95% CI [-0.5;2.7]) in the frontal cortex and 0.8 mL/cm 3 (95% CI [-0.5;2.1]) in the hippocampus, corresponding to a 5-6 % increase. Next, we investigated whether changes in SV2A binding were associated with mystical-type experiences during the session or persisting effects three months later. A linear mixed-effects model estimated an nominal increase in SV2A binding of 0.5 mL/cm 3 per 10 units increase in mysticality scores (from the LVM shown in Figure) for the frontal cortex (p = 0.16) and 0.3 mL/cm 3 for the hippocampus (p = 0.28). We also examined whether there was an association between the latent variable positive persisting effects (Figure) and SV2A binding changes: β = +2.6 points per mL/cm 3 for both the frontal cortex and the hippocampus (p > 0.37). The association with negative effects (log-transformed, Figure) was -21% per mL/cm³ (p = 0.05).
This study is the rst to investigate whether a single psychoactive dose of psilocybin induces synaptic plasticity in the healthy human brain. While the overall increase in cerebral SV2A density was not statistically signi cant one week after the psilocybin session, session setting markedly in uenced the results. Participants who underwent the session in a designated calm intervention room with curated music showed a 5-6% increase in SV2A binding in the frontal cortex and hippocampus-aligning with the study's targeted effect size-whereas those scanned during the session did not show this increase. The setting also affected subjective experiences. Participants in the MR scanner reported lower scores on mystical-type experiences and had lower positive persisting effects three months later. Moreover, our exploratory analyses found a numerical increase in SV2A binding with higher mysticality score. This observation should be further investigated as a prede ned hypotheses in future studies, including both larger sample sizes and patients with, e.g., major depressive disorder. Our ndings suggest that in response to psilocybin, synaptic plasticity may be in uenced by supporting psychological effects of the setting and the emotional valence of the psychedelic experience. Mystical-type experiences during psilocybin interventions have been linked to long-term positive effects, including enhanced well-being in healthy individuals, reduction in anxiety and depressive symptom in patient with major depressive disorderand terminal cancer. While these effects could result from differences in psilocybin dosage and subjective drug intensity, prior studies suggest otherwise. Roseman et al. did not nd similar effects for sensory perceptual experiences, and Gri ths et al. reported that mystical effects remained signi cant even after adjusting for drug intensity. Additionally, a recent study in 233 patients with depression found that the association between symptom reduction and Oceanic Boundlessness scores remained consistent across three different psilocybin doses (1, 10, and 25 mg). Mediation analyses by both Ross et al. and Gri ths et al. also support that therapeutic effects are partially driven by mystical-type experiences. Thus, the positive effects of psilocybin in both healthy individuals and psychiatric patients may be linked to neurobiological modulations of synaptic connections that depend on the acute subjective effects. The emotional valence of these experiences appears particularly important-not only when comparing mystical-type experiences (e.g., ASC-OBN, MEQ30) to sensory-perceptual changes, but also when looking into the subscales within these facets. Our latent variable model (Fig.) showed that subscales with less emotional valence (Disembodiment, Transcendence of Time and Space, Ineffability) had the lowest weighting. This is consistent with Disembodiment being the only OBN subscales that did not differ between responders and non-responders in psilocybin-assisted depression treatment. Similarly, McCulloch et al. found that while the MEQ30 predicted positive effects at three months, the subscales Transcendence of Time and Space and Ineffability were not statistically signi cant. Together, these ndings underscore the importance of fostering positive experiences during the intervention. Both our study and that of Studerus et al.highlight the impact of the physical session environment, but as most contemporary psychedelic therapy takes place in designated intervention rooms, future research should focus on optimizing psychological support strategies. This includes music selection to facilitate emotional statesand building strong therapeutic rapport, which has been shown to enhance positive treatment outcomes. Some important aspects of the present study should be considered. We conducted the study in healthy individuals who may exhibit less pronounced synaptic plasticity-promoting effects due to homeostatic plasticity mechanisms. In contrast, patients with major depressive disorder show lower SV2A binding, with de cits correlating with symptom severity. Thus, psilocybin may induce stronger synaptic upregulation in clinical populations, potentially restoring lost synapses, while exerting smaller effects in healthy individuals. The timing of the follow-up PET scan is another important consideration. Preclinical studies have shown that psychedelics can induce neuroplasticity within 24 hours. However, a human PET study of ketamine found no SV2A changes 24 hours post-administration. Our choice of a one-week follow-up scan was informed by data from pig brain studies nding that synaptic upregulation is higher one week than one day after psilocybin. We cannot exclude that psilocybin induces an acute increase in SV2A, re ecting early synaptic remodeling, which later stabilizes or is partially reversed due to synaptic pruning. The dynamics of the neuroplastic process may also differ between healthy individuals and clinical populations, depending on the balance between plasticity and homeostasis. Few other studies have reported in vivo SV2A changes following pharmacological interventions in humans. We recently reported that intake of the selective serotonin reuptake inhibitor escitalopram was associated with a time-dependent effect on SV2A, suggesting a gradual enhancement of synaptic density (28). Similarly, recent cocaine use is associated with higher SV2A density (46), whereas cannabis use is not. Perhaps different classes of psychoactive drugs have distinct and time-varying effects on synaptic plasticity, with stimulants and psychedelics promoting synaptic upregulation or synaptic vesicle capacity through different mechanisms. Some methodological limitations of the study should be noted. Our paired PET scan design enables within-subject comparisons and was powered based on a same-day test-retest study. However, two other SV2A neuroimaging studies with healthy individuals have reported lower SV2A in the second scan session; both when re-scanning the same day (48) or four weeks later. Both these studies found lower V T values at the second scan, in the range of -1% to -8%, and for BP ND in the range of -5% to -14%. The underlying mechanism of this bias remains unclear, but in the absence of a placebo arm, we may have underestimated the effect of psilocybin to increase SV2A. Second, in our group sequential design, the main analysis used a stricter signi cance threshold (p = 0.028) to maintain 5% type I error rate. We did not pre-specify thresholds for exploratory analyses; adjustment depends on the correlation with the primary outcome-0.05 may be appropriate for independent outcomes, while 0.028 applies to highly correlated ones. However, since the trial stopped for futility rather than e cacy, using an unadjusted threshold is less concerning. Finally, we did not account for uncertainty in the LVM-weighted scores, which may underestimate p-values.
study represents an important step in understanding the persisting effects of psilocybin on the human brain. We show that the psychedelic experience is shaped by the session environment and Figures
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