Psilocybin-induced changes in cerebral blood flow are associated with acute and baseline inter-individual differences

Data were pooled from three randomized, double-blind, placebo-controlled, cross-over studies conducted at the Psychiatric University Hospital Zurich. The final analysed sample comprised N = 70 healthy, right-handed adults (mean age 25.3 years, 29 female) who passed medical, psychiatric, and drug-screening assessments; participants with current or lifetime major psychiatric disorders, close family history of such disorders, pregnancy, or more than ten lifetime psychedelic uses were excluded. In the cross-over design each participant received oral placebo and psilocybin in counterbalanced order, with sessions at least 10 days apart. Psilocybin doses administered were 0.16 mg/kg (n = 31), 0.20 mg/kg (n = 10), and 0.215 mg/kg (n = 29); placebo formulations varied across studies but were lactose or mannitol-based. All participants gave informed consent and studies had ethical approval. Behavioural measures included the Symptom Checklist 90-R (SCL-90-R) completed at screening to estimate baseline psychopathological symptoms (global score and subscales) and the Five Dimensional Altered States of Consciousness questionnaire (5D-ASC) completed 360 minutes post administration to capture the acute subjective psychedelic experience across 11 subscales and a global score. Neuroimaging used a Philips 3 T scanner with T1-weighted anatomy and pseudo-continuous ASL (pCASL) acquired 80–100 minutes after drug administration; sequence parameters and image resolutions varied slightly across participants and studies. Standard preprocessing steps were applied (realignment, smoothing, perfusion calculation, normalization to MNI space); three participants were excluded for extreme T2*-corrected gray matter CBF values and one for failed co-registration, yielding the reported final sample. CBF quantification produced voxel-wise aCBF maps and rCBF maps, the latter obtained by dividing each voxel's aCBF by the individual's mean gray-matter CBF within a gray-matter mask. Statistical analyses first tested for dose effects using one-way ANOVAs; because dose did not significantly affect CBF outcomes, dose was not included in subsequent analyses. Paired t-tests compared psilocybin versus placebo for voxel-wise rCBF and aCBF with cluster-level family-wise error (FWE) correction (p < 0.05, primary voxelwise p < 0.001, k > 250); a more conservative peak-level threshold was used for aCBF clusters. Extracted cluster eigenvalues (psilocybin minus placebo) were Pearson-correlated with behavioural measures. To examine whether baseline (placebo) CBF related to psilocybin-induced changes without mathematical coupling, the Oldham method was used, correlating the mean of the two measurements with their difference. Correlations were treated as exploratory and reported at p < 0.05 uncorrected.

Imaging comparisons revealed both increases and decreases in rCBF after psilocybin versus placebo. Increased rCBF was observed in frontal and limbic regions, notably the inferior frontal gyrus and hippocampus (cluster-level pFWE < 0.05). Decreased rCBF was detected predominantly in parietal regions (postcentral gyrus) and temporal cortex (superior temporal gyrus); the temporal lobe showed a mixed pattern with increased rCBF in the fusiform gyrus alongside decreases in the superior temporal gyrus. For absolute perfusion, no psilocybin-induced increases were found; instead, aCBF showed widespread decreases in parietal (postcentral gyrus, rolandic operculum), limbic (putamen), and frontal regions (middle frontal gyrus), with these clusters surviving FWE correction. Dose did not significantly affect the CBF outcomes, and body weight showed no consistent influence on rCBF once dose was accounted for; an initial partial correlation suggested a negative association between body weight and decreased aCBF (r = -0.33, p = 0.005), but a full-brain regression did not identify a significant effect and body weight was not included thereafter. Behavioural–neural correlations produced several associations centred on the inferior frontal gyrus (IFG). Baseline global symptom severity (SCL-90-R global score) correlated positively with psilocybin-induced increased rCBF in the right IFG (r = 0.25, p = 0.034), indicating larger rCBF increases in participants reporting higher baseline symptom levels. Multiple 5D-ASC measures correlated with increased rCBF in the IFG: the 5D-ASC global score (r = 0.30, p = 0.001), experience of unity (r = 0.26, p = 0.029), disembodiment (right IFG r = 0.33, p = 0.005; left IFG r = 0.24, p = 0.048), and complex imagery (right IFG r = 0.29, p = 0.016; left IFG r = 0.26, p = 0.031). A single participant with an extreme score drove the impaired control and cognition correlation; exclusion of that participant rendered the association non-significant. For aCBF, elementary imagery was negatively correlated with reduced aCBF in the left postcentral gyrus (r = -0.25, p = 0.04), meaning higher elementary imagery corresponded to a stronger decrease in aCBF in that region. Examining baseline neurobiology, placebo rCBF in regions later showing psilocybin-induced increases was positively associated with the magnitude of psilocybin-induced rCBF increases: participants with higher placebo rCBF in the inferior frontal gyrus and hippocampus showed larger psilocybin-induced rCBF increases (r = 0.46, p < 0.001). No significant associations were found between placebo and psilocybin values for decreased rCBF (r = 0.05, p = 0.652) or aCBF changes (r = 0.07, p = 0.584). Finally, placebo CBF measures correlated with some subjective outcomes: placebo rCBF in the left IFG showed a modest negative association with disembodiment (r = -0.24, p = 0.049), and placebo aCBF in the left postcentral gyrus was positively associated with reported audio-visual synesthesia (r = 0.24, p = 0.046). Correlation analyses were exploratory and reported without correction for multiple comparisons.

Rieser and colleagues interpret their findings as evidence that both baseline neurobiological organisation and baseline psychological state relate to the acute neural and subjective effects of psilocybin. The pattern of results replicates earlier reports of psilocybin-induced rCBF increases in frontal and limbic regions and decreases in parietal regions, while temporal regions showed heterogeneous effects. The authors highlight the inferior frontal gyrus as a focal region linking psilocybin-induced neural changes to subjective phenomena: increased rCBF in the IFG was associated with stronger reports of unity, disembodiment, complex visual imagery, and other 5D-ASC dimensions. They suggest the IFG's known involvement in emotion recognition, empathy and bodily awareness may help explain why activity changes there correlate with emotional and perceptual aspects of the psychedelic experience. Baseline rCBF measured under placebo was also predictive: participants with higher resting rCBF in frontal cortices and hippocampus exhibited larger psilocybin-induced rCBF increases, leading the authors to propose baseline rCBF as a candidate predictive biomarker for individual sensitivity to psilocybin's neural effects. They link this to prior work showing that baseline BOLD connectivity can predict psychedelic-induced connectivity changes and propose exploring baseline measures in clinical trials as part of a personalised-medicine approach. The discussion also contrasts rCBF and aCBF findings, noting that rCBF (after global normalisation) appeared more sensitive to brain–behaviour associations, and addresses the methodological debate about global signal removal in perfusion studies. The authors acknowledge several limitations: analyses were exploratory and not corrected for multiple comparisons, so results require replication in hypothesis-driven work; the correlational design precludes directional or causal inferences; and single measurements of baseline and psilocybin conditions may be affected by intra-individual variability, so repeated measures could improve reliability. They position the study as a large ASL dataset that narrows knowledge gaps about how baseline characteristics and acute subjective states relate to psilocybin-induced CBF changes and as a basis for future investigations into mechanisms and predictive biomarkers for psychedelic-assisted therapy.