European Neuropsychopharmacology

Anxiety and maladaptive fear remain difficult to treat, and despite initial promising findings, evidence regarding the anxiolytic and translational potential of oxytocin (OT) remains inconsistent. In a preregistered, randomized, double-blind, placebo-controlled, parallel-group pharmaco-fMRI study in 67 healthy men, we tested whether intranasal OT reduces post-exposure subjective fear during prolonged naturalistic viewing a horror movie comprising independently defined low-, medium-, and high-fear segments. OT reduced subjective fear following naturalistic threat exposure after accounting for pre-exposure baseline ratings. Neuroimaging analyses revealed that OT attenuated recruitment of the dorsolateral prefrontal cortex particularly during higher fear, and enhanced coupling of this region with the bilateral amygdala. At the large-scale network level, OT increased communication between frontoparietal/default-mode control networks and subcortical/limbic networks during high fear indicating more integrative fear regulation. A whole-brain fear neuromarker (CAFE) further confirmed intensity-dependent OT effects. Together, these findings indicate that OT modulates post-exposure fear experience and fear-related neural dynamics in ecologically valid contexts.

Although non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated a therapeutic-relevant potential by enhancing mood recovery and fear extinction, its influence on neural dynamics during naturalistic, sustained fear processing remains unclear. In this study, we employed a randomized, sham-controlled, parallel-group design involving 63 participants (taVNS: n = 33; sham: n = 30) who provided continuous subjective fear ratings (1170 timepoints) while watching a 10-minute fear-inducing video, with simultaneous fNIRS recordings. We employed: (1) a convolutional neural network (CNN) to decode fear ratings from frontal activations, (2) validation of stimulus-evoked activity comparing fNIRS with fMRI signal, (3) dynamic conditional correlation analysis to assess taVNS-induced connectivity changes, and (4) moderation analysis to examine anxiety state effects. Behaviorally, taVNS significantly attenuated fear responses during four threat phases by content analysis: T1 (ghost appearance), T2 (escape sequence), T3 (sudden threat emergence) and T4 (suicide scene). Neurally, taVNS suppressed medial prefrontal cortex (mPFC) activation during escape (T2) and disrupted the typical fear coupling between fear experience and brain activity. Furthermore, taVNS enhanced intra-mPFC functional connectivity, suggesting a potential neural basis for modulating subjective threat appraisal. Additionally, state anxiety significantly moderated brain-behavior relationships. These findings demonstrate that taVNS attenuates fear responses through modulation of mPFC engagement and strengthening frontal network integration. Our results highlight taVNS as a promising neuromodulatory intervention for fear-related disorders (e.g., anxiety disorder), particularly as an early adjunct to exposure-based therapies, warranting further clinical validation.

Anhedonia and motivational impairment are central features of major depressive disorder, yet the neural processes linking reward information to sustained goal-directed behaviour remain insufficiently understood. Using functional magnetic resonance imaging, we examined representations of reward levels during sustained effort expenditure (a construct in the RDoc framework) as a distinct component of reward processing in depressive patients under escitalopram treatment. Twenty-eight unmedicated patients with a current depressive episode and forty-three healthy control participants underwent fMRI scanning at two time points three weeks apart; patients started escitalopram immediately after the first measurement. Across participants, sustained effort expenditure engaged midbrain reward circuitry (ventral tegmental area, VTA), even in the absence of immediate reinforcement. A targeted analysis also revealed changes in activity of the dorsal raphe nucleus (DRN) in patients. Increases in VTA activity were associated with improvements in clinician-rated depressive symptoms, whereas self-reported anhedonia remained unchanged. By isolating neural mechanisms supporting sustained goal-directed behaviour, the study identifies novel and clinically relevant imaging phenotypes of reward processing and a potential pathway of escitalopram treatment in depression.

Psilocybin shows therapeutic promise for several psychiatric disorders, but the acute perceptual and cognitive alterations produced by conventional doses (10-25 mg) require in-clinic supervision, which limits scalability. Whether the therapeutically relevant pharmacology of psilocybin can be separated from its hallucinogenic activity remains unresolved. To address this gap, we conducted a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study to characterize the safety, pharmacokinetics and pharmacodynamics of low doses of psilocybin. Fifty-six healthy adults received a single oral dose of psilocybin (0.5, 1.0, 1.5, 2.5, 3.5 or 4.0 mg) or matching placebo across seven sequential cohorts, with each dose escalation reviewed by a Drug Safety Review Committee. All participants completed the study with no serious adverse events or discontinuations. Treatment-emergent adverse events were comparable to placebo and most prominently arose as somnolence. Plasma psilocin appeared rapidly with a median time to maximum concentration < 1 h with dose-proportional exposure and a short terminal half-life. Subjective drug effects were dose-related and became distinguishable from placebo at doses at or below 2.5 mg. Peak subjective ratings increased with dose, while any signs of hallucinations or altered-states scores remained low and not different than placebo. Psychophysiological engagement was confirmed by a clear dose-dependent pupillary dilation while cognitive performance (attention, vigilance, working memory, impulse control) showed no dose-dependent decrement and state anxiety did not increase at any dose. These findings indicate that the perceptible pharmacology of psilocybin can be dissociated from significant perceptual alterations and cognitive impairment at low doses. They further support controlled investigations in outpatient Phase 2 studies evaluating the safety and feasibility of repeated, self-administered low-dose psilocybin. ClinicalTrials.gov #NCT07710027

Major depressive disorder (MDD) is a severe psychiatric disorder that affects more than 350 million people worldwide, yet its biomolecular mechanisms are incompletely understood, and clinically applicable markers remain elusive. To shed new light on the underlying pathophysiology of MDD across multiple research disciplines, we first used a biochemical fingerprinting approach with human hair (the first 3 cm cut from the scalp) to identify changes in the total set of detectable metabolites and lipids (metabolipidomics) using quadrupole time-of-flight mass spectrometry (qToF-MS). In this study, we focused on endocannabinoid (ECB)-related lipid compounds and identified 7 candidate markers that differed between depressed and non-depressed female participants. Two phosphatidylinositols, namely PI 24:0 and PI 37:4, showed dose-dependent associations with the severity of depressive symptoms. Finally, to bridge hair findings with previously reported results in blood, we tested associations between changes in identified ECB-related compounds and parameters of mitochondrial respiratory activity in peripheral blood mononuclear cells. We found 17 significant associations, with the strongest effects for the lipids PI 24:0, MGDG-O 16:3, PG 12:0, and PI 37:4. Our approach not only identified novel associations between endocannabinoid (ECB)-related lipid dysregulation and impaired mitochondrial energy metabolism in MDD but also revealed ECB-related lipids as a possible surrogate marker of impaired bioenergetic metabolism in MDD, at least in immune cells. More research is needed to replicate these findings, ideally by testing reversibility in longitudinal intervention studies and by including both sexes in larger cohorts.

Major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are prevalent, chronic, and disabling mental health conditions which are difficult to treat. Ketamine has demonstrated effect for improving depression and PTSD symptoms independently but reports often overlook focused comorbid improvement of these symptoms within individuals. To address this, we assessed blood-based biomarker and psychological changes following low-dose oral ketamine treatment for adults with MDD alone (n=14) and comorbid MDD+PTSD (n=21). Before treatment, the MDD clinical group presented with more severe depression, lower serotonin levels and higher kynurenine levels than the MDD+PTSD group. Post-treatment there were no detectable differences in the biological response between clinical groups, with combined analysis revealing common decreases in circulating brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF-A). Additionally, post-treatment, both clinical groups showed improvements in anxiety, stress, social functioning, suicidal ideation, and general well-being measures, as well as individual improvements in depression scores and PTSD symptoms in the MDD- and PTSD-containing groups, respectively. Collectively, this study presents additional evidence that low-dose oral ketamine treatment can be effective for MDD and MDD+PTSD, individually and comorbidly, and that both MDD and PTSD clinical groups responded in the same biological manner.

Social connection is fundamental to human wellbeing. Serotonergic psychedelics such as lysergic acid diethylamide (LSD) acutely heighten subjective connectedness, yet their effects on real-time social connection remain poorly understood. Using EEG hyperscanning in a randomized, double-blind, placebo-controlled crossover study, we recorded neural activity simultaneously from both members of healthy romantic couples (N=25) who received LSD (50 g) or placebo together, across resting and interactive states. LSD increased subjective connectedness, including feelings of love, closeness, trust, and being "in sync," while reducing loneliness, compared to placebo. This affiliative shift dissociated from the drugs pharmacokinetic time-course, remaining elevated as subjective intensity and plasma concentration declined. In parallel, LSD increased inter-brain synchrony during shared rest, carried specifically by theta-band amplitude-envelope coupling. Importantly, this effect survived two complementary controls. First, it exceeded coupling between unrelated individuals and second the effects depended on contemporaneous neural alignment rather than shared drug-induced dynamics. Exploratory analyses showed that romantic partners with greater resting synchrony reported greater feelings of connectedness. These findings provide the first evidence that a psychedelic enhances brain-to-brain coupling between people, linking a pharmacologically induced state of felt connection to a measurable signature shared across interacting brains.

Background: Serotonin has been implicated in cognitive flexibility and pathological perseverative thinking (PT), including rumination, worry, and obsessions. However, evidence remains fragmented across pharmacological manipulations, clinical populations, and outcome measures. This multilevel meta-analysis examined whether serotonergic interventions influence PT and cognitive flexibility. Methods: Preregistered and following PRISMA guidelines, we synthesized studies investigating three classes of serotonergic manipulations: acute tryptophan depletion (ATD), serotonin elevation via selective serotonin reuptake inhibitors (SSRIs), and classic serotonergic psychedelics. Three multilevel random-effects meta-analyses with cluster-robust variance estimation were conducted: (A) effects of ATD on cognitive flexibility (N = 266; 10 effect sizes), (B) effects of serotonin elevation on cognitive flexibility (N = 654; 15 effect sizes), and (C) effects of serotonin elevation on pathological perseverative thinking (N = 1,100; 20 effect sizes). Across analyses, the total sample comprised 2,030 participants and 45 effect sizes. Results: ATD did not significantly impair cognitive flexibility (g = 0.15, 95% CI [-0.07, 0.38], p = .23), and no moderation by task type, sex, or age was observed. Serotonin elevation similarly did not improve cognitive flexibility (g = -0.07, 95% CI [-0.36, 0.22], p = .63), with no significant performance differences emerging between SSRIs, classical psychedelics, or tryptophan enrichment. In contrast, serotonin elevation was associated with a significant medium-to-large reduction in perseverative thinking (g = -0.58, 95% CI [-0.76, -0.41], p < .001). Notably, while both pharmacological classes effectively reduced cognitive rigidity, SSRIs demonstrated a marginally smaller magnitude of symptom reduction compared to acute psilocybin interventions (p = .081). Furthermore, samples with a higher proportion of female participants showed larger reductions in perseverative thinking ({beta} = -1.86, p = .014), while worries exhibited marginally smaller reductions relative to obsessions ({beta} = 0.42, p = .055). Publication bias tests were non-significant across analyses. Conclusions: Serotonergic interventions robustly reduce perseverative thinking but do not consistently alter performance on laboratory measures of cognitive flexibility. These findings suggest that serotonin may influence cognitive-emotional rigidity and the subjective experience of repetitive thought more strongly than objective executive task performance. The dissociation between task-based and phenomenological outcomes aligns with contemporary models of serotonergic plasticity and highlights perseverative thinking as a potentially transdiagnostic therapeutic target of serotonergic interventions.

Background: Substance use is common among individuals with depression. Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but current clinical guidelines have discouraged TMS treatment for individuals with depression and co-occurring substance use given concerns for limited efficacy. However, limited data exists on whether substance use affects response to TMS. Methods: Using electronic health record data from patients who received a standard course of TMS for major depressive disorder at an academic medical center, we investigated associations between substance use frequency and response to TMS, defined as change in Patient Health Questionnaire-9 (PHQ-9) scores. Substance use frequency was extracted for alcohol, cannabis, nicotine, stimulants, benzodiazepines, opioids, inhalants, psychedelics, and other drugs. We performed ANCOVA and multiple regression analyses to predict change in PHQ-9 score based on substance use frequency, controlling for pre-TMS PHQ-9 score, age, sex, and number of TMS sessions received. Results: We extracted data from 219 TMS courses. Alcohol was the substance used most commonly (34.2%), followed by prescription benzodiazepines (28.3%), and prescription stimulants (21.0%). Across all substance categories, substance use was not associated with change in PHQ-9 score (all p > 0.05, Cohens d=0.00 to 0.30). In multiple regression models to compare individual levels of substance use frequency (e.g., daily use vs. no use), level of substance use was not associated with change in PHQ-9 score (all p > 0.05). The range of plausible effects of substance use frequency on PHQ-9 change was generally below the minimal clinically important difference for PHQ-9, suggesting substance use was unlikely to have a meaningful clinical effect on antidepressant response to TMS. Conclusions: Low to moderate substance use does not have a clinically significant effect on antidepressant response to TMS. Low-level substance use should not exclude individuals with depression from receiving TMS.

Accelerated 5x5 repetitive Transcranial Magnetic Stimulation (rTMS; five stimulation sessions per day for five days) is an effective treatment for Major Depressive Disorder (MDD), and has efficacy comparable to conventional once-daily rTMS. Considering the heterogeneity of symptoms in patients with MDD, it is critical to determine how accelerated 5x5 and conventional rTMS affect depression symptom domains. We compared symptom change over time in patients treated with either accelerated 5x5 rTMS (25 total sessions, n = 40) or conventional once-daily rTMS administered over six weeks (30 total sessions, n = 135). Accelerated 5x5 patients received either prolonged intermittent theta burst stimulation (piTBS) or personalized "resonant frequency" (RF) stimulation. Mixed-effects linear models were built to compare the two protocols, with the primary outcome variables being the Inventory of Depression Symptomology Self-Report (IDS), the Ruminative Response Scale (RRS), and the Profile of Mood States - Brief (POMS), yielding measures of 14 unique depression symptom domains. Both protocols led to similar improvements in all 14 depression symptom domains (all interaction term p-values > .05). Subsequent exploratory analyses demonstrated that accelerated 5x5 and conventional rTMS may differ in the time courses of their effects on anxiety, rumination, mood, depression, and vigor (p-values < .05, uncorrected). These results suggested that accelerated 5x5 rTMS has a similar efficacy in alleviating 14 depression symptom domains compared to conventional once-daily rTMS, and that either protocol may be appropriate for MDD patients with a variety of symptom profiles.

Background: Individuals receiving buprenorphine treatment for opioid use disorder (OUD) remain at high risk for treatment discontinuation and return to opioid use. Transcranial magnetic stimulation (TMS) has shown efficacy in reducing craving and substance use in other substance use disorders, but its application in OUD remains limited and the neural mechanism underlying its therapeutic effects is poorly understood. Determining the feasibility and generalizability of TMS in patients receiving buprenorphine - the most commonly prescribed medication for OUD - is therefore critical. This protocol aims to address these issues in a clinical trial of weekly TMS sessions for OUD. Methods: We will enroll up to 120 individuals with OUD taking buprenorphine in a randomized, single-blind, sham-controlled trial of left dorsolateral prefrontal cortex (DLPFC)-targeted intermittent theta burst stimulation (iTBS). Participants will receive active or sham iTBS weekly (2 sessions of 1800 pulses each applied once per week x 8 weeks, 16 sessions total) with pre- and post-iTBS assessments (10, 12, 20 weeks) of craving, opioid use, and treatment retention. A subset of individuals will undergo optional pre- and post-iTBS neuroimaging. The study will be conducted at an academic medical center and a private outpatient TMS clinic. Aims: Our primary aim is to determine whether 16 sessions of active iTBS applied to the left DLPFC results in reduced craving and opioid use, and higher treatment retention, relative to sham. In a secondary aim, we will also examine whether iTBS-related changes in craving are associated with changes in functional connectivity between the left DLPFC and both the dorsal striatum and anterior cingulate cortex. Discussion: By evaluating the feasibility and efficacy of a weekly TMS protocol that aligns with routine care and focuses on patients maintained on buprenorphine, this study addresses key limitations of prior TMS research in OUD. Furthermore, the inclusion of neuroimaging will help characterize the neural mechanisms underlying TMS-related changes in craving. Trial registration: This clinical trial is registered at ClinicalTrials.Gov; ID NCT07457489; date of registration: 03/02/2026.

Major depressive disorder (MDD) is strongly associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, systemic inflammation, and gut microbiota dysbiosis. Although selective serotonin reuptake inhibitors such as escitalopram are standard treatments, their efficacy is often constrained by partial response and gastrointestinal adverse effects. In this 12-week, randomized, double-blind, placebo-controlled trial, we evaluated the clinical efficacy and microecological mechanisms of adjunctive Lactiplantibacillus plantarum PS128 (PS128; 6*1010CFU/day) in MDD patients on stable escitalopram therapy. Adjunctive PS128 significantly enhanced clinical response compared to placebo, yielding substantial reductions in HAMD-17 and MADRS, alongside a higher remission rate. 16S rRNA sequencing and PICRUSt2 profiling revealed that PS128 enriched key short-chain fatty acid producers (Faecalibacterium, Coprococcus), counteracting the Klebsiella expansion seen in placebo. Functionally, PS128 up-regulated neuroprotective cofactor, B vitamins, biosynthesis and down-regulated the neurotoxic kynurenine pathway. Network analysis demonstrated that PS128 maintained a resilient, integrated microbial co-occurrence topology, whereas the placebo network showed structural segregation. This stabilized ecosystem attenuated peripheral inflammatory signaling and normalized salivary cortisol levels. Overall, adjunctive PS128 augments escitalopram efficacy by enhancing gut network stability, supporting cellular energetics, and modulating neuroendocrine activity, offering a promising multimodal strategy for MDD.

Suicidal behavior results from complex behavioral and biological changes. Previous cross-sectional studies indicate that proinflammatory immunobiological factors are often increased in close temporal proximity to a suicide attempt. Suicidal individuals may also exhibit a biological trait vulnerability to stress and inflammation, due to persistent epigenetic modifications. We enrolled 130 individuals with major depressive disorder (MDD), 83 with suicidal behavior at intake, and followed them for 12 months with up to eight clinical assessments. Quantification of plasma inflammatory markers and metabolites was performed by high-sensitivity electrochemiluminescence and Ultra High-Performance-Liquid-Mass Spectrometry (UPLC-MS), respectively. Epigenetic changes were identified using Illumina EPIC arrays. We identified 15 genes with altered DNA-methylation associated with suicidal behavior and attempts at baseline. Childhood trauma predicted lifetime suicide attempts and was associated with altered methylation of seven genes. Increased neutrophils and lower plasma serotonin at baseline predicted future suicide attempts over the following year (neutrophil estimate = 0.42, P = 0.016; serotonin OR = 0.58, 95% CI: 0.39-1.13). Utilizing biomarkers from baseline and epigenetic data from the genes with highest predictive values (STBD1 ,PRDM8, and TRIM15), we achieved an area under the curve (AUC) of 0.84 for suicide attempts over the year. Suicidal behavior in MDD was associated with specific epigenetic signatures. Several of the identified genes, such as MAD1L1, have been implicated in psychiatric disease, suicidal behavior and the immune response. These findings support the usefulness of epigenetic and immunometabolic blood markers for identifying suicidal individuals in clinical settings, potentially enhancing preventative efforts.

Background Negative symptoms in schizophrenia spectrum disorders (SSD) remain insufficiently treated and require novel therapeutic approaches. Oxytocin may improve negative symptoms, although its effects appear highly context-dependent according to the social salience hypothesis. We conducted a randomized, triple-blind, placebo-controlled pilot study combining intranasal oxytocin with mindfulness-based group therapy (MBGT), hypothesizing that the positive social context of MBGT would enhance oxytocin-related effects. Methods 47 participants with SSD (34% female) were randomized to receive either 24 IU oxytocin (MBGT+OXT; n = 26) or placebo (MBGT+PLA; n = 21) before four MBGT sessions. Primary outcome was negative symptoms assessed with the Positive and Negative Syndrome Scale negative subscale (PANSS-N) at post-intervention and 4-week follow-up. Secondary outcomes included the Brief Negative Symptom Scale (BNSS), Self-Evaluation of Negative Symptoms Scale (SNS), and additional clinical measures. Linear mixed models estimated within- and between-group effects. Results Overall dropout rate was 14.89%, with one dropout potentially treatment-related. Blinding was successful. Participants completed 95.63% of sessions. Only the MBGT+OXT group showed significant improvements in PANSS-N from baseline to post-intervention (d = -0.74) and follow-up (d = -0.77), with a small between-group effect at follow-up (d = 0.39). BNSS total improved significantly only in the MBGT+OXT group from baseline to post-intervention (d = -0.88) and follow-up (d = -0.91), with between-group effects favoring MBGT+OXT at follow-up (d = -0.38). No serious adverse events occurred. Conclusions These findings suggest, oxytocin combined with MBGT may improve negative symptoms in SSD and support further large-scale trials. Clinical Trials Registration: https://clinicaltrials.gov/study/NCT06136390, Registration number: NCT06136390

Background: Hyperbolic tapering is an increasingly recognized approach for discontinuing serotonin reuptake inhibitor (SRI) antidepressants that involves non-linear dose reductions with equal stepwise reductions in serotonin transporter (SERT) occupancy to mitigate withdrawal symptoms. Its theoretical basis is the hyperbolic relationship between SRI dose and SERT occupancy reported in radioligand imaging studies. Hyperbolic tapering implicitly assumes that changes in SERT occupancy approximate changes in biologic effect and withdrawal risk. Because SERT occupancy plateaus across the therapeutic dose range of SRIs, this framework predicts relatively small biologic effects and withdrawal risk within this range. However, SERT occupancy influences serotonergic activity only indirectly via its effects on extracellular serotonin concentrations, and the relationship between these two variables is poorly characterized. Methods: We developed a two-pathway clearance model derived from mass-action kinetics to evaluate the steady-state relationship between SERT occupancy and extracellular serotonin concentrations under chronic SRI treatment. Results: Our analysis indicates that serotonin concentrations increase hyperbolically as transporter occupancy increases, suggesting that biologically meaningful differences in serotonergic signaling persist across the therapeutic dose range of SRIs despite plateauing occupancy. Conclusions: Our model predicts a hyperbolic relationship between SERT occupancy and extracellular serotonin concentrations, suggesting that changes in occupancy may not map proportionally onto serotonergic effect. These findings provide a potential mechanistic explanation for dose-dependent clinical effects of SRIs despite plateauing transporter occupancy and generate testable hypotheses regarding antidepressant tapering strategies. Empirical validation is warranted.

BackgroundSerotonergic psychedelics are advancing as psychiatric treatments, yet acute responses vary between individuals and the contribution of sex, a fundamental biological variable, remains largely unexamined. MethodsWe pooled two double-blind, placebo-controlled studies in healthy volunteers (N = 72; 31 male, 41 female) comparing psilocybin 15 mg, 2C-B 20 mg, and LSD 50 {micro}g. Linear mixed models tested sex differences in acute subjective effects (visual analogue scales), retrospective altered-states ratings (5D- and 11-ASC), empathy (Multifaceted Empathy Test), and peak plasma blood concentrations (Cmax, AUC), with treatment, sex, their interaction, as fixed factors, and age as a covariate. ResultsFemale participants reported numerically higher subjective ratings than male participants on most measures. After adjustment for age, sex differences remained significant for feeling under the drugs influence, reduced vigilance, and impaired control and cognition, with medium-to-large effects. These effects were largely consistent across the three drugs. No sex differences emerged on any empathy measure or in peak drug concentrations. ConclusionsFemale participants may experience more intense acute subjective effects and greater perceived impairment under psychedelics, independent of age and not explained by drug exposure. These preliminary findings, implicating pharmacodynamic rather than pharmacokinetic mechanisms, have implications for dosing, informed consent, and safety monitoring, and underscore the need to treat sex as a biological variable in adequately powered psychedelic trials.

Background: Cannabis is one of the most widely used psychoactive substances worldwide. {Delta}-tetrahydrocannabinol ({Delta}-THC) is the main contributor to cannabis-induced effects such as euphoria, anxiety, and psychotomimetic effects, and is metabolized by several hepatic enzymes, including CYP3A4. There are interindividual differences in how cannabis affects users, which have substantial genetic contributors. Methods: We examined how real-time effects of {Delta}-THC on psychotomimetic measures and on subjective effects of "high", sadness and anxiety in 188 healthy volunteers in a laboratory infusion paradigm, relate to polygenic risk scores (PRS) for cannabis lifetime use (CanLU), cannabis use disorder (CanUD), and CYP3A4 expression. Results: CYP3A4 expression PRS was significantly associated with {Delta}-THC-induced psychotomimetic effects. Genetic liability to use and misuse cannabis is potentially associated with lower {Delta}-THC-induced psychotomimetic symptoms. CanLU PRS nominally predicted enhanced {Delta}-THC-induced "high", while CanUD PRS predicted it to be lower. Conclusions: Our findings suggest that genetic liability to produce more CYP3A4 enzyme may be associated with faster {Delta}-THC degradation and the consequential diminution of the latter's effects. Nominal effects suggest that aversive outcomes may reduce cannabis use and use disorder genetic liability, and that CanUD subjects may need higher {Delta}-THC doses to experience euphoria ("high"). In total, this study provides novel insights regarding some of the specific genetic factors that influence interindividual variability in {Delta}-THC effects, mainly via {Delta}-THC metabolism.

Transdiagnostic psychiatric research on reward-guided learning has largely focused on simple associative processes, leaving it unclear whether or how higher-level processes are disrupted. Here, we studied how abstraction, the ability to extract relevant features from complex information, and metacognition, the ability to monitor and evaluate one's own mental processes, map onto specific transdiagnostic dimensions. Using an online sample (N = 249), we examined associations between these processes and three cross-culturally robust transdiagnostic dimensions derived from a large existing dataset (N = 19,505): Compulsive hypersensitivity, Social withdrawal, and Addictive behaviours. Computational modelling of an abstract representation learning task with confidence judgments revealed that Compulsive hypersensitivity was negatively associated with both abstraction ability (pboot = 0.003) and metacognitive sensitivity (pboot = 0.005), while Social withdrawal was positively associated with metacognitive sensitivity alone (pboot = 0.002). Moreover, transdiagnostic dimensions revealed more coherent associations with higher-order cognition than symptom-level analyses, highlighting the added value of examining psychopathology at the factor rather than the symptom level. These findings portray a hierarchical view of cognitive dysfunctions in psychopathology and point to representational and metacognitive processes as potential targets for transdiagnostic intervention.

Importance There is increasing interest in the potential of psilocybin to treat mental health and neurodevelopmental conditions. At high doses, the therapeutic benefit of psilocybin is linked to greater functional connectivity or integration between large-scale brain networks which underpin mood, emotion and cognition. However, it is unknown how the brain responds to psilocybin in autism - a condition characterised by both altered functional connectivity and differential response to drugs. Thus, a first step before clinical trials of psilocybin involving autistic people, is to evaluate the response of the autistic brain to psilocybin, initially at low dose. Objective Low doses of psilocybin were used to test the hypothesis that the functional connectivity of large-scale resting-state brain networks respond differently in autistic and non-autistic adults. Design The PSILAUT study had a pseudo-randomised, cross-over, double-blind, case-control design. There was no evaluation of clinical efficacy. PSILAUT was not a Clinical Trial according to UK regulations. Data collection was conducted from January 2023 to August 2024. Setting Single-centre, study conducted at the Institute of Psychiatry, Psychology & Neuroscience, Kings College London, London, United Kingdom. Participants Adult (> 18 years) participants with and without an autism spectrum disorder (ASD) diagnosis were recruited and matched for age, sex and IQ. Autistic participants were included if they had an existing diagnosis (DSM-IV, DSM-5 or ICD-10 criteria). Exposures A single oral dose of 2 or 5 mg psilocybin or (inactive) placebo administered on separate visits at least one week apart. Main Outcomes and Measures Resting-state fMRI was acquired to investigate the change in functional connectivity within and between brain networks, as measures of network integrity and integration, respectively. Results A total of 67 participants were recruited (18-58 years at first visit; 30 non-autistic participants, mean [SD] age, 30.0 [8.3] years, 15 males [50%] and 37 autistic participants, mean [SD] age, 28.6 [9.2] years, 19 males [51%]). We report for the first time that the autistic brain responds differently to low doses of psilocybin, despite no group differences in network connectivity in the baseline placebo condition. 5 mg psilocybin elicited the greatest shifts in functional connectivity in both groups, but in different directions. In non-autistic participants only, on average, after 5 mg psilocybin within-network connectivity of the frontoparietal ({beta} = -0.053, T = -2.73, FDR-corrected P value = 0.027, Cohen d = -0.71) and limbic networks ({beta} = -0.087, T = -2.59, FDR-corrected P value = 0.021, Cohen d = -0.61) decreased. In contrast, in autistic participants, 5 mg psilocybin increased between-network connectivity (i.e. integration) of higher-order and attentional networks, but decreased connectivity between the same networks in non-autistic participants (default mode and frontoparietal networks, dose x group interaction: {beta} = 0.053, T = 2.91, FDR-corrected P value = 0.042; dorsal and ventral attention networks, dose x group interaction: {beta} = 0.059, T = 2.31, FDR-corrected P value = 0.015). Across the whole sample, the extent to which psilocybin elicited an increase in connectivity between higher-order ({beta} = 0.33, T = 2.16, FDR-corrected P value = 0.036) and attentional ({beta} = 0.36, T = 2.43, FDR-corrected P value = 0.036) networks was positively correlated with core autistic traits quantified using the Autism Quotient. Conclusions and Relevance Functional brain networks that support mood, emotion and cognition are more responsive to low dose psilocybin in autistic adults compared to non-autistic adults. Given that increased network integration is associated with clinical utility, future applications of psilocybin in autistic people should include the evaluation of low doses.

Emotion regulation is critical for adaptive functioning and mental health. Functional neuroimaging studies have identified distributed frontal, parietal, and limbic networks involved in emotion regulation, particularly during cognitive reappraisal. However, the neurochemical mechanisms underlying individual differences in emotion regulation remain poorly understood. The endogenous opioid system is a promising candidate because -opioid receptor systems acts as a stress buffer and modulates emotional responses to both rewarding and aversive stimuli We used positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to examine whether baseline -opioid receptor (MOR) availability is associated with haemodynamic responses during emotion regulation through reappraisal. Participants underwent [11C]carfentanil PET imaging to quantify MOR availability and subsequently completed an fMRI task involving passive viewing of emotional images and cognitive reappraisal of their emotions during image viewing As expected, fMRI revealed engagement of the dorsolateral prefrontal cortex and inferior parietal lobule during cognitive reappraisal. Baseline MOR availability predicted blood oxygenation level-dependent (BOLD) responses in frontal, temporal, and parietal regions: individuals with higher MOR availability showed a larger difference between regulation and viewing trials in the temporal pole, angular gyrus, anterior insula, thalamus, and inferior frontal gyrus. These associations were driven primarily by stronger responses during passive viewing, although some regions also showed evidence of reduced responses during active reappraisal. These findings suggest that higher endogenous opioid tone is associated with stronger recruitment of distributed frontal, temporal, and parietal networks during emotional stimulus processing as well as attenuation of activity in some of these regions during cognitive reappraisal. Thus, while higher MOR availability is associated with enhanced neural responsiveness to emotional stimuli, these responses can nevertheless be effectively modulated through deliberate emotion regulation.