Patrick MacDonald Fisher

Lysergic acid diethylamide (LSD) is a potent psychedelic with increasing therapeutic interest, yet qualification of target engagement using in vivo neuroimaging has not yet been performed. Using simultaneous positron emission tomography–magnetic resonance imaging technology, we describe multiple brain actions of LSD in seven healthy volunteers blinded to LSD dose received. Here we show that LSD occupies 5-HT2AR with a high affinity and increases both global cerebral blood flow (CBF) and internal carotid artery flow. LSD also decreases global connectivity, which was negatively associated with changes in CBF. We observe an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. We contrast our CBF and global connectivity findings and their relation in a separate cohort of 25 participants administered psilocybin, highlighting key consistencies and differences. By establishing the dose–occupancy relation of LSD in humans, our findings provide insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from psilocybin.

Classic psychedelics, including lysergic acid diethylamide (LSD), are currently under investigation for the treatment of major depressive disorder (MDD). Cognitive dysfunction is common in MDD, but effects of psychedelic treatment on cognitive brain function, measured by magnetic resonance imaging, are sparsely reported. The present study investigated effects of LSD treatment on working memory-related brain function in patients with MDD. In a randomized, double-blind, parallel-group trial, 43 patients with MDD received either two low-dose (25 µg) or two high-dose (100 and 200 µg) oral LSD treatments 4 weeks apart. Functional magnetic resonance imaging during an n-back working memory task was conducted before and approximately 1 week after the second treatment. The treatment × time interaction effect on working memory-related brain responses (2-back and 1-back vs . 0-back) was assessed using linear mixed effects models. We also explored associations between brain responses and depression severity, task performance, and subjective psychedelic experiences. Compared with low-dose treatment, high-dose LSD treatment significantly increased working memory-related brain responses ( p = 0.007) within task-activated regions, including the dorsolateral prefrontal cortex, parietal cortex, insula, striatum, and thalamus. Working memory-related brain responses correlated with task performance and subjective perceptual changes but not treatment response. Our observations provide the first evidence that LSD treatment in patients with MDD affects cognitive brain function. Contrary to our hypothesis, high-dose LSD significantly increased brain responses. These responses positively correlated with task performance, suggesting a potential LSD-induced boost in neural function. The absence of an association with depressive symptoms indicates that task-related brain activity may underlie different mechanisms than changes in mood. Trial registration: Clinicaltrials.gov Identifier: NCT03866252.

Population mean maps (PMMs) are commonly shared in neuroimaging, allowing researchers to assess relationships between studies by computing spatial correlations between maps. However, determining the statistical significance of these correlations is challenging because spatial autocorrelation and voxel-wise noise variance are often unknown and spatially heterogeneous. Here we introduce Dual Permutation (DP), a flexible non-parametric method for computing p-values for spatial correlations between PMMs derived from distinct subject cohorts. DP operates by permuting or sign-flipping subjects within each modality to create surrogates that preserve the spatial structure of the noise. The resulting surrogate PMMs are used to generate an empirical null distribution of the correlation coefficient. DP builds upon unimodal subject-level permutation, a well-established approach in neuroimaging that preserves spatially heterogeneous noise structure. We show that the problem is more complex than generally appreciated because different null distributions can arise when signal is present in one modality but not the other; we introduce a method called Maximum Difference in Variance (MaxDV) to address this issue. We derive analytical results demonstrating that DP preserves the variance of the correlation coefficient under the null hypothesis across a broad range of spatial autocorrelation, voxel scaling, noise characteristics, and group-level designs. Using a diverse set of real neuroimaging datasets spanning volumetric, surface-based, and region-of-interest analyses, we show that DP accurately controls the false positive rate. Although DP requires subject-level data and cannot be applied when only PMMs are available, we also demonstrate that PMM-only analyses can produce both false positive and false negative findings. A publicly available implementation of DP is available in FreeSurfer as the mri_dualperm tool.

Complex cognitive functions rely on coordinated communication between distributed brain regions, yet capturing these interactions as they evolve over time remains challenging. Traditional analyses of functional brain connectivity largely rely on correlations in signal amplitude, which are sensitive to noise and artifacts such as head motion. Here, we introduce a mixture modeling approach that focuses on the phase of brain signals, allowing dynamic patterns of large-scale synchronization in brain phase coherence networks to be studied directly and in their entirety. We lay the mathematical and conceptual groundwork for phase modeling and introduce the complex angular central Gaussian mixture model, providing a principled way to analyze phase-based interactions across the brain. Applied to functional MRI data, the model identifies recurring states of brain-wide synchronized activity that reliably distinguish cognitive tasks and generalize across previously unseen individuals, without requiring any task labels during training. These results show that modeling signal phase offers a clean and informative view of brain synchronization dynamics, opening avenues for studying large-scale neural coordination.

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 (0.3 mg/kg) 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. Overall, we found no statistically significant increase in SV2A density. However, 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. ClinicalTrial : NCT03289949.

A prominent theory of psychedelics is that they increase brain entropy. Thirteen studies have evaluated psychedelic effects on fMRI brain entropy, each applying a distinct measure. Here we evaluated these metrics in an independent 28-participant healthy cohort with 121 pre- and post-psilocybin fMRI scans. We assessed relations between brain entropy and objective and subjective psychedelic drug effects using linear mixed-effects models. All metrics were evaluated using two parcellation strategies and 7 denoising pipelines. We observed consistent significant positive associations for Shannon entropy of the spatial eigendistribution of the time by voxel matrix, path-length, instantaneous correlations, brain-state switching, and sample entropy at short time-scales. We consistently did not observe significant effects for 8 of 14 entropy metrics and observe inconsistent positive effects for Lempel-Ziv complexity of the BOLD signal. Brain entropy quantifications showed limited inter-measure correlations. Our observations support a nuanced acute psychedelic effect on brain entropy, empirically demonstrating that these metrics do not reflect a singular construct.

Background: Patients with chronic cluster headache (CCH) suffer from poor sleep, which may impact their brain microstructure and parenchymal clearance of waste products. Psilocybin has shown promise for the treatment of CCH and has been linked to increased neuroplasticity with possible influences on brain microstructure. Aims: To investigate the effects of psilocybin on sleep, brain water diffusivity, and microstructure in CCH. Methods: Eleven CCH patients underwent diffusion-weighted MRI and subjective sleep quality assessment with the Pittsburgh Sleep Quality Index (PSQI) before and 1 week after three psilocybin administrations (0.14 mg/kg) spaced 1 week apart. Measures taken prior to intervention were also compared to 24 healthy controls, and subjective sleep quality was related to brain microstructure and diffusivity across groups. Results: We found that sleep was poor in CCH patients, but improved after psilocybin treatment (CCH mean PSQI change (SD) = –2.50 (2.1), p _FWER = 0.015). When analyzing brain microstructure and water diffusivity in conjunction, we found differences between CCH patients and controls, which were primarily driven by differences in grey matter. On average, psilocybin intervention in CCH patients was not associated with statistically significant changes in brain microstructure or water diffusivity. However, most patients exhibited lower white matter diffusivity and neurite volume after intervention. Subjective sleep quality showed borderline significant correlations of moderate effect size with brain microstructure and water diffusivity. Conclusion: Subjective sleep quality improved in CCH patients after psilocybin and showed some evidence of an association with measures of brain microstructure and water diffusivity. ClinicalTrials.gov identifiers: Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH; NCT04280055) and The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2; NCT03289949).

Classical psychedelics have regained interest for their potential to treat psychiatric and neurological disorders, and explore neural mechanisms supporting perception, cognition, and mood. Acute psychedelic effects have been linked to increases in brain complexity and entropy, but it is unclear if these changes are specific to psychedelics or reflect more general psychoactive effects. Here, we examined whether brain complexity and entropy metrics can identify features specific to the psychedelic state. Using resting-state fMRI from three placebo-controlled crossover trials (N=79; 255 sessions), we compared LSD, psilocybin, and mescaline with psychostimulants MDMA and d-Amphetamine. Compared to stimulants, psychedelics produced significant increases in meta-state complexity, short-timescale multiscale entropy, and dynamic conditional correlation entropy. Both drug classes increased Lempel-Ziv and spatial complexity, and decreased absolute modularity. Our findings highlight psychedelic-specific effects on brain signals that distinguish the acute psychedelic state from other psychoactive drug effects and may be relevant for understanding their therapeutic potential.