Psychedelic compound N,N-Dimethyltryptamine (DMT) is renowned for inducing highly immersive experiences, often including encounters with seemingly sentient presences. While such phenomena are well documented, immersion under psychedelics remains conceptually underdefined and phenomenologically underexplored. Here we apply micro-phenomenology to characterize immersion under DMT as a structured continuum from subtle to gross forms of immersion, and to examine how perceived presences arise within this continuum. Twenty-three participants received 20 mg intravenous DMT during simultaneous fMRI-EEG acquisition, followed by detailed micro-phenomenological interviews focused on the temporal unfolding of experience. Micro-phenomenological analysis methods yielded 125 phenomenological categories describing structural dimensions, including sensory and amodal faculties, spatial organisation, self-world configuration, and modes of social relatedness. Dynamic analysis revealed reliable developmental patterns, with bodily effects typically preceding visual and auditory ones, and perceived presences emerging only after multisensory integration and 3D spatial characteristics had developed, illustrating a hierarchical relationship between subtle and gross forms of immersion. Perceived presences varied widely in sensory modality, semantic complexity, and relational mode. These findings show immersion under DMT as a dynamic, constructive process, providing precise structural features for future neurophenomenological modelling, and supporting the view that DMT research may inform our understanding of immersive experience across other aetiologies, including ordinary experience of the world.

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet many patients have inadequate responses to current treatments. Dimethyltryptamine (DMT), a serotonergic psychedelic with rapid onset and short duration, shows promise as a potential antidepressant (AD), although clinical evidence in MDD remains limited. We conducted a phase IIa, double-blind, placebo-controlled, randomized clinical trial to evaluate the efficacy and safety of intravenous DMT (SPL026; DMT fumarate) in adults with moderate-to-severe MDD. Participants received a single 21.5-mg dose of DMT or placebo infused over 10 min, along with supportive psychotherapeutic support, followed by a 2-week assessment. A subsequent open-label phase offered all participants a second DMT dose. The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) at 2 weeks. Secondary outcomes included response (≥50% reduction in MADRS score) and remission (MADRS ≤ 10). A total of 34 participants were randomized, 17 to placebo-active and 17 to active-active. At 2 weeks, the DMT group showed a significantly greater reduction in MADRS score than placebo (mean difference = -7.35; 95% CI = -13.62 to -1.08; P = 0.023). In the open-label phase, AD effects persisted up to 3 months, with no significant differences between those who received one versus two doses. Adverse events were mostly mild to moderate, commonly infusion site pain, nausea and transient anxiety. No serious adverse events occurred. A single dose of DMT with psychotherapeutic support produced a rapid, significant reduction in depressive symptoms, sustained up to 3 months. The treatment was well-tolerated and safe. ClinicalTrials.gov registration: NCT04673383 .

Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator underpinning various psychological and physiological processes, with dysregulation implicated in numerous psychiatric disorders. Non-invasive measurement of endogenous 5-HT release in the living human brain is essential to advance understanding of the serotonergic system. The combination of Positron Emission Tomography (PET) neuroimaging of serotonergic receptors with pharmacological and behavioural challenges that stimulate endogenous 5-HT release, offers a unique approach to quantify 5-HT dynamics in vivo. In 2010, Paterson and colleagues concluded in a thorough review that measures of 5-HT release were constrained by limitations in the sensitivity of available tracers and potency of pharmacological challenges. Novel tracers combined with optimised pharmacological challenge paradigms have demonstrated sensitivity to changes in endogenous 5-HT, enabling reproducible detection of acute 5-HT release in both preclinical and human studies in the last 15 years of research. These include the use of agonist radioligands with preferential binding to high-affinity receptor states, such as [11C]AZ10419369 and [11C]Cimbi-36, antagonist tracers, such as [18F]Altanserin, refined challenge designs using pharmacological 5-HT releasers, such as fenfluramine and amphetamine, and the integration of hybrid PET/MR imaging to assess neurovascular aspects. These advances have shifted the field from questioning feasibility to addressing optimal strategies for measuring serotonergic dynamics.

Abstract Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is largely unknown. In an exploratory, placebo-controlled, within-subjects, electroencephalography (EEG), and magnetic resonance imaging (MRI) study in 28 healthy, entirely psychedelic-naive participants, anatomical and functional brain changes are detected from one-hour to one-month after a single high-dose (25 mg) of psilocybin. Increases in cognitive flexibility, psychological insight, and well-being are seen at one-month. Diffusion tensor imaging (DTI) done before and one-month after 25 mg psilocybin reveals decreased axial diffusivity bilaterally in prefrontal-subcortical tracts that correlate with decreases in brain network modularity (fMRI) over the same month. Enduring functional brain changes are largely absent, but network modularity change (numerical decrease) negatively correlates with well-being change (significant increase), in line with previous findings in depression. Increased cortical signal entropy (EEG) at 1- and 2-hours post-dosing predicts improved psychological well-being at one-month. Next-day psychological insight mediates the entropy to well-being relationship. All effects are exclusive to 25 mg psilocybin; no effects occur with a 1 mg psilocybin placebo.

We investigated ketamine's neuroplastic effects in healthy human subjects using integrated Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) measures before and 1-8 days after a single psychedelic dose of ketamine (1 mg/kg, intravenous). Eleven male participants underwent two PET/MRI scans with [11C]-UCBJ (synaptic density/plasticity), 1H-MRS (glutamate and GABA) and resting-state fMRI (intrinsic brain activity, functional connectivity), before and after ketamine. While group-level analyses showed no significant increases in PET synaptic markers, ketamine administration resulted in significantly elevated glutamate levels within the anterior cingulate cortex (ACC). Functional connectivity analyses revealed reduced coupling between the ACC and the dorsolateral prefrontal cortex (dlPFC) and increased coupling between the ACC and the amygdala in the days following ketamine administration. Our multimodal analysis revealed that participants showing an increase in [11C]-UCBJ volume distribution (VT), a putative index of synaptic plasticity, showed a correlated reduction in intrinsic activity within regions belonging to the default mode network (DMN). By linking molecular, cellular and network-level changes, our results point to the DMN as a central hub where ketamine may reshape brain hierarchies in the long term, providing new directions for understanding its therapeutic mechanisms and developing targeted treatments.

Importance:The involvement of the serotonin system in the pathophysiology of schizophrenia has been proposed for over 60 years, but there has been no prior study to test if there is altered serotonin release in vivo in schizophrenia (to the authors' knowledge). Objective:To investigate serotonin release in vivo in schizophrenia and its association with negative symptoms. It was hypothesized a priori that frontal cortex serotonin release capacity would be lower in schizophrenia compared with healthy controls and that this would be associated with more severe baseline negative symptoms. Design, Setting, and Participants:This was a single-center case-control neuroimaging study conducted in London, UK. All participants had dynamic 90-minute [11C]Cimbi-36 positron emission tomography (PET) scans at baseline and 3 hours after oral administration of d-amphetamine 0.5mg/kg. Data were collected between 2015 and 2024. Participants included stable adult outpatients with DSM-5 schizophrenia (antipsychotic free or taking antipsychotics with negligible affinity for 5-hydroxytryptamine receptor 2A [5-HT2A] receptors) and healthy controls matched for age, sex, and body mass index. Main Outcomes and Measures:The primary neuroimaging outcome was the group difference in serotonin release capacity, prespecified as the percentage change in frontal cortex [11C]Cimbi-36 binding potential between the baseline and d-amphetamine scans. Results:A total of 54 individuals were included, 26 with DSM-5 schizophrenia (mean [SD] age, 33.3 [9.1] years, 16 male [62%]; 21 not taking antipsychotic medication [81%]) and 28 healthy controls (mean [SD] age, 32.0 [9.5] years, 19 male [68%]). Frontal cortex serotonin release was significantly greater in the group with schizophrenia compared with healthy controls (18.0%; 95% CI, 2.5%-33.6%; P = .02; Cohen d = 0.69). In schizophrenia, greater frontal cortex serotonin release was correlated with more severe baseline negative symptoms (Brief Negative Symptom Scale: Pearson r = 0.42; P = .04) and poorer functioning (Social Functioning Scale: Pearson r = -0.42; P = .04). Exploratory analyses showed significantly greater frontal cortex serotonin release in deficit schizophrenia, characterized by primary and enduring negative symptoms, compared with healthy controls (mean difference = 32.3%; FDR-corrected P value = 0.001; Cohen d = 1.10) and nondeficit schizophrenia (mean difference = 28.9%; FDR-corrected P value = 0.004; Cohen d = 0.89). These findings were all replicated in 21 individuals with schizophrenia not taking antipsychotic medication. Baseline cortical [11C]Cimbi-36 binding (indexing baseline cortical 5-HT2A receptor levels) was unaltered in schizophrenia. Conclusions and Relevance:This case-control study found that serotonergic dysfunction in the pathophysiology of schizophrenia was associated with negative symptoms, suggesting the regulation of serotonin release as a target to treat negative symptoms. Results of the exploratory analysis suggest particularly marked serotonergic dysfunction in the subgroup with deficit schizophrenia.

Rationale: Major depressive disorder (MDD) shows marked sex differences in prevalence, symptomatology, and treatment response. However, women remain underrepresented in many clinical trials, and sex-specific treatment outcomes are rarely examined. Objectives This study reanalyzed data from a randomized controlled trial comparing psilocybin and escitalopram for MDD to evaluate sex differences across multiple psychological domains. Methods We reanalyzed data from a six-week, double-blind randomized controlled trial comparing psilocybin with escitalopram in adults with moderate-to-severe MDD. Post-treatment depressive symptoms (MADRS, QIDS-SR-16, BDI), anhedonia (SHAPS), anxiety (STAI), thought suppression (WBSI), and well-being (WEMWBS) were modeled as a function of sex, treatment condition, their interaction, and baseline symptom severity. Sexual dysfunction severity (PRSexDQ-SALSEX), assessed only at the six-week follow-up, was analyzed separately as an ordinal outcome. Results Sex-related patterns emerged for anxiety and anhedonia. Women receiving psilocybin showed greater reductions in anxiety than men (STAI: 95% CrI − 17.5 to − 3.29), whereas women receiving escitalopram showed greater reductions in anhedonia than men (SHAPS: 95% CrI − 4.63 to 0.00). For the remaining continuous outcomes, sex differences were generally small and uncertain. Sexual dysfunction severity was lower overall in the psilocybin group than in the escitalopram group and lower in women than in men, although the treatment-by-sex interaction was not significant. Conclusions This reanalysis identified domain-specific sex-related patterns in anxiety and anhedonia, suggesting that responses to psilocybin and escitalopram may differ between women and men. These preliminary findings support adequately powered, sex-balanced, and hormone-informed trials of serotonergic treatments for MDD.

Abstract A central challenge in neuroscience is understanding how the human brain is organised to support optimal functioning and adaptability. One approach to characterise complex brain dynamics is by artificially perturbing whole-brain models. Here, we asked whether whole-brain organisation under perturbation in major depressive disorder (MDD) changes after intervention with psilocybin and escitalopram. First, we built whole-brain models of pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) and obtained an initial generative effective connectivity (GEC) matrix for each individual. Then, we employed systematic and local artificial perturbations across intensities, re-optimised each model to create a response GEC (GECr), and assessed the extent of brain reorganisation by quantifying the brain network reconfiguration index (NRI). Our results showed that the global brain NRI increases with psilocybin and decreases with escitalopram. Across sessions and interventions, higher global NRI was related with localised perturbations in brain areas orchestrating the brain’s hierarchical dynamics. Traditional approaches complemented our investigation. Our findings suggest distinct neural changes following each treatment for MDD. The increase in brain reorganisation under perturbation following psilocybin is consistent with greater brain flexibility and changeability, whereas the decrease following escitalopram suggests more stabilised brain dynamics. Overall, perturbation-induced brain NRI may represent a useful approach for uncovering neural changes following different interventions for depression.

Abstract In recent decades, the psychedelic psilocybin has been studied as a potential treatment for major depressive disorder (MDD), offering an alternative to traditional antidepressants. However, the brain changes underlying the clinical effects of different interventions remain unclear. Here, we investigated the effects of psilocybin and a conventional antidepressant, escitalopram, from the double-blind randomised controlled trial (DB-RCT) - NCT03429075 - on the brain’s hierarchical organisation. Using pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) we built whole-brain models and obtained a generative effective connectivity (GEC) matrix for each patient. Based on the GEC, we measured the level of non-equilibrium brain dynamics by quantifying the deviation from the fluctuation-dissipation theorem (FDT) and performed complementary analysis on brain segregation and asymmetry. Our results showed opposite reconfigurations of the hierarchical non-equilibrium brain dynamics following each treatment. Additionally, baseline measures effectively distinguished responders from non-responders within each treatment. These findings suggest that the deviation of the FDT may serve as a marker for differentiating the effects of psilocybin and escitalopram in MDD treatment, overall, contributing to the understanding of therapeutic mechanisms of depression.

INTRODUCTION:Positron Emission Tomography (PET) imaging is a close ally of Precision Medicine, and it has been proven to be indispensable in the field of Psychiatry. This imaging modality may also present an important role in understanding Neurodevelopmental disorders and their link to Psychiatric conditions, with new highly selective binders being used currently in research. PET imaging requires the administration of radiopharmaceuticals, where the radioisotope is in incorporated into a highly selective binder. Dosimetry and injected activity optimisation play a crucial role in the field of PET imaging as they allow to determine the radiation dose absorbed by target and non-target tissues, and determine the lowest amount required to deliver images with diagnostic quality and obtain reliable quantitative data, without overexposing patients. The aim of this research is to investigate the feasibility of reducing the injected activity of the [11C]-(+)-PHNO and [11C]UCB-J radiopharmaceuticals, for patients with neurodevelopmental disorders who undergo brain imaging in the PET-Magnetic Resonance (MR) scanner, without compromising quantitative accuracy of outcome measures. RESULTS:No statistically significant differences were found when comparing the 1/2 to 1/6 datasets with the full injected activity [11C]-(+)-PHNO dataset. Furthermore, the findings obtained from investigating the impact of low injected activity administrations of [11C]UCB-J revealed that it is possible to reduce the administered activity by 1/2, when the clinical outcome measure under evaluation is the binding potential relative to non-displaceable volume (BPND). When the outcome measure under investigation is the standard uptake volume ratio (SUVR), it is possible to decrease the injected activity to 1/3, for [11C]UCB-J. CONCLUSIONS:The simulation and analysis methodologies deployed in this project are suitable for investigating scans with low injected activity for tracers with cortical and striatal uptake, when the outcome measure assessed is the BPND or the SUVR. Whilst the data suggests that imaging with low injected activity is achievable, the efficacy of the investigation is highly dependent on the algorithm used to reconstruct the images, the outcome measure and the radiopharmaceutical used to acquire the PET-MR scans. For the [11C]UCB-J radiopharmaceutical, it is possible to decrease the injectable activity to 1/3 of the original administration without compromising the SUVR.

Despite decades of neuroscience research and significant investment in addiction neuroimaging, clinical outcomes for individuals with substance use and behavioural addictions remain poor. Only 1.8% of people with substance use disorders receive effective treatment, highlighting a major disconnect between mechanistic understanding and clinical utility. This paper calls for a reorientation of addiction neuroscience, from a predominantly diagnostic focus toward a theragnostic framework, in which biomarkers are used to stratify patients, guide treatment decisions, and predict outcomes. We argue that the integration of translational neuroimaging biomarkers, particularly fMRI, EEG, and PET, within psychedelic addiction research offers a unique and timely opportunity to catalyse this shift. Psychedelic compounds such as psilocybin represent a new class of therapeutics capable of engaging neuroplasticity, reward and emotional processing, and cognitive control networks central to addiction pathophysiology. We review how acute and pre–post neuroimaging paradigms can index pharmacodynamic effects and longer-term treatment response and propose a roadmap for embedding biomarkers in early and late phase clinical trials. Drawing on ongoing studies at the Centre for Psychedelic Research at Imperial College London, we outline how multimodal biomarkers are being co-developed alongside clinical trials in gambling and opioid use disorders to identify biotype-specific responses and build a deeply phenotyped treatment population. We argue that these biomarkers, if validated, could serve as regulatory-grade tools for drug theragnostic co-development, mirroring successful models in oncology and neurology. Importantly, we emphasise that realising this vision will require robust multi-stakeholder collaboration, including academia, industry, regulatory agencies, funders, healthcare systems, and patient groups alongside dedicated investment to build a scalable theragnostic infrastructure for addiction research and medicine. In conclusion, psychedelic therapy offers more than symptomatic relief, it presents a vehicle for transforming how we diagnose, treat, and understand addiction. By embracing theragnostic principles and prioritising biomarker integration, addiction medicine has the potential to move towards personalised and precision-guided care.

Setting up a psychedelic study can be a long, arduous, and Kafkaesque process. Researchers are faced with a host of challenges in this rapidly evolving field, necessitating a range of considerations that remain largely unstandardised. Many of the complexities inherent to psychedelic research also challenge existing assumptions around, for example, approaches to psychiatric prescribing, the conceptual framing of the placebo effect, and definitions of selfhood. This review paper aims to formalise these unique considerations by addressing the sociocultural, political, legal, pharmacological, safety, study design and experiential facets inherent to a psychedelic study. We bring together several of the major psychedelic research teams across the United Kingdom, identify continuing areas of debate, and provide a practical, comprehensive, experience-based guide, with recommendations for policymakers and future researchers intending to set up a psychedelic research study or clinical trial.

BACKGROUND:Anorexia nervosa is a debilitating eating disorder with high mortality and chronicity rates owing to the paucity of effective existing treatments. Several clinical trials using psilocybin therapy have demonstrated therapeutic efficacy and safety in psychiatric conditions, including anorexia nervosa. AIMS:This study aimed to further assess the safety, feasibility and potential efficacy of psilocybin therapy in anorexia nervosa. METHOD:This single-blind, within-individual pilot study recruited 21 females with anorexia nervosa, who underwent three dosing sessions with oral psilocybin (COMP360) over 6 weeks in a fixed order (1 mg, 25 mg, 25 mg), alongside talk therapy and adjunctive to treatment as usual. Adverse events were monitored throughout the study. Primary clinical outcome measures were global Eating Disorder Examination Interview (EDE) and Readiness and Motivation Questionnaire (RMQ) precontemplation scores. Primary time points for the EDE were the 6-week final visit, 3-month follow-up and 6-month follow-up; and for the RMQ, they were the 6-week final visit and comparison between dosing days. Global EDE Questionnaire scores were a key secondary outcome. Key time points were the 6-week final visit and comparison between dosing days. There was a 12-month remote follow-up. RESULTS:Psilocybin was well tolerated by all participants. The most common adverse events were headache, nausea and dizziness. Two serious adverse events (suicide attempts) were reported for one participant within the 6-12-month period. Relative to baseline, participants displayed significant improvements in their eating disorder symptoms (EDE scores: p < 0.0001, d = 0.98, 6 months) and motivation to change (RMQ scores: p = 0.0017, d = 0.65, 12 months). However, there was a large variation in improvement and maintenance during the follow-up. CONCLUSIONS:This study further provides preliminary support for the feasibility, safety and potential efficacy of this intervention to treat adult females with anorexia nervosa, and warrants further investigation in larger and more rigorously designed studies.

Determining the scale of neural representations is a central challenge in neuroscience. While localized representations have traditionally dominated, evidence suggests information is also encoded in distributed, hierarchical networks. Recent research indicates that the hierarchy of causal influences shaping functional patterns serves as a signature of distinct brain states, with implications for neuropsychiatric disorders. Here, we first explore how whole-brain models, guided by the thermodynamics of mind framework, estimate brain hierarchy and how perturbing such models enables the study of in-silico transitions represented by static functional connectivity. We then apply this to major depressive disorder, where different brain hierarchical reconfigurations emerge following psilocybin and escitalopram treatments. We build resting-state whole-brain models of depressed patients before and after interventions and conduct a dynamic sensitivity analysis to explore brain states’ susceptibility—measuring their capacity to change—and their drivability to healthier states. We show that susceptibility is on average reduced by escitalopram and increased by psilocybin, and that both treatments promote healthier transitions. These results align with the post-treatment window of plasticity opened by serotonergic psychedelics and the similar clinical efficacy of both drugs in trials. Overall, this work demonstrates how whole-brain models of brain hierarchy can inform in-silico neurostimulation protocols for neuropsychiatric disorders.

Major depressive disorder (MDD) is a leading cause of suicide and disability. Better understanding changes to serotonin2A receptors (5-HT2ARs) in MDD and suicide may help to improve treatments. We systematically reviewed and meta-analysed positron emission tomography (PET), single photon emission computed tomography (SPECT) and post-mortem radioligand binding studies of cortical 5-HT2ARs in MDD and suicide. Databases were searched from inception to August/September 2024. Binding data were extracted and pooled before random-effects meta-analyses of mean difference (Hedges’ g) and variance were undertaken. Simple linear regression was performed to investigate the relationship between receptor binding and depression severity at baseline in PET and SPECT studies. We also assessed study quality and tested for evidence of publication bias. Data on 556 MDD patients or suicide victims and 526 controls from 31 studies were included. Cortical 5-HT2AR binding was significantly lower in living MDD patients, who had not taken antidepressants for between one week and forever, than controls in frontal, prefrontal, cingulate, anterior cingulate and, upon sensitivity analysis, temporal cortex (Hedges’ g = –0.40 to –0.57). In frontal and cingulate regions, binding effect size correlated with depression severity at baseline. There was study-level evidence of lower regional binding in never-medicated MDD patients than controls which, upon exploratory meta-analysis, reached significance in anterior cingulate cortex. Most PET or SPECT studies were of good or fair quality. The results of most post-mortem analyses were negative and included studies were of variable quality. There was limited evidence of publication bias. In vivo 5-HT2AR binding is reduced in MDD in frontal, cingulate and temporal cortex. This finding is based mainly on studies that used antagonist or inverse agonist radiotracers.

This systematic review and meta-analysis aims to explore a possible role of gamma-aminobutyric acid (GABA) and glutamate, as measured by Magnetic Resonance Spectroscopy (MRS), in the treatment outcomes of people with Major Depressive Disorder (MDD). Despite the prevalence of MDD and various treatment modalities, the neurobiological mechanisms of each remain poorly understood. We synthesised data from 41 longitudinal studies comprising 918 individuals with MDD, spanning four primary treatment modalities: selective serotonin reuptake inhibitors (SSRIs), ketamine, repetitive transcranial magnetic stimulation (rTMS), and electroconvulsive therapy (ECT).Pooled analyses revealed a significant increase in Glx levels post-treatment across modalities, with this effect persisting in responder-only subgroups and analyses restricted to prefrontal regions. In contrast, no consistent changes were observed in GABA or glutamate levels following treatment. These results suggest that modulation of Glx, but not bulk GABA or glutamate, may be a common neurobiological mechanism underlying therapeutic response in MDD. However, a role for GABAergic systems cannot be excluded, as functionally relevant changes may occur without detectable shifts in overall concentration. We recommend future studies prioritise reporting by responder status and employ higher-field MRS techniques to more precisely characterise treatment-related bulk metabolite changes.

OBJECTIVE:Psilocybin is an emerging intervention for depression that may be at least as effective as selective serotonin reuptake inhibitors (SSRIs), but effects of the two treatments on the neural correlates of emotional processing have never been directly compared. METHODS:The authors assessed neural responses to emotional faces using blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) in two groups with major depression. One group (N=25; 9 women and 16 men) received two dosing sessions with 25 mg psilocybin plus 6 weeks of daily inert placebo, and the second group (N=21; 6 women and 15 men) received 6 weeks of escitalopram plus two dosing sessions with a nonpsychoactive (placebo) dose of 1 mg psilocybin. Both groups had equal psychological support throughout: 3 hours of preparation, one in-person integration session following the psilocybin dosing sessions, and two further integration sessions conducted via video call or telephone. An emotional face fMRI paradigm was completed before treatment and at the 6-week posttreatment primary end point (3 weeks following psilocybin dosing sessions). RESULTS:Patient group (psilocybin versus escitalopram) interacted with time point (before versus after treatment) on a distributed set of cortical regions. Post hoc within-condition analyses showed that posttreatment BOLD responses to emotional faces of all types were significantly reduced in the escitalopram group, with no change or a slight increase in the psilocybin group. Analyses of amygdala responsivity showed a reduction of response to fearful faces in the escitalopram group, but lesser effects for the psilocybin group. CONCLUSIONS:Despite large improvements in depressive symptoms in the psilocybin group, psilocybin therapy had only a minor effect on brain responsiveness to emotional stimuli. These results are consistent with prior findings that the antidepressant action of SSRIs is often accompanied by a reduction in emotional responsiveness, but this effect may not occur in psychedelic therapy.

BACKGROUND:Preclinical work suggests that chronic nicotine/tobacco use is associated with reductions in serotonin within the hippocampus, yet no research has yet shown an association of smoking behaviors and alterations in brain serotonin in humans in vivo. METHODS:We therefore analyzed existing [11C]DASB PET data from the Cimbi Database to compare the availability of the serotonin transporter (SERT) in the hippocampus, midbrain (including the raphe), and neocortex of 60 healthy non-smokers, 15 ex-smokers, and 11 current smokers who also provided blood samples for determination of plasma tryptophan load. Because SERT availability is considered to be negatively associated with extracellular serotonin levels, we hypothesized that current smokers would exhibit greater SERT availability than ex-smokers and non-smokers. RESULTS:There was a significant main effect of group on SERT binding (DASB BPND) values in the bilateral and left hippocampus, and a trend toward such in the right hippocampus. Post hoc ANOVAs revealed that current smokers exhibited greater hippocampal DASB BPND than both non-smokers and ex-smokers, while the latter 2 groups did not differ. There were no group effects on DASB BPND within the midbrain or global neocortex. Finally, there was no significant group effect on plasma tryptophan load. CONCLUSIONS:This study provides the first in vivo evidence that current smoking may be associated with elevated hippocampal SERT binding-possibly reflecting lower synaptic serotonin concentrations, and that this change may normalize following smoking cessation.