Journal of Psychopharmacology

Psilocybin is a classic psychedelic and a novel treatment for mood disorders. Psilocybin induces dose-dependent transient (4-6 hours) usually pleasant changes in perception, cognition, and emotion by non-selectively agonizing the 5-HT2A receptors and negatively regulating serotonin reuptake, and long-term positive antidepressant effect on mood and well-being. Long-term effects are ascribed to the psychological quality of the acute experience, increase in synaptodensity and temporary (1-week) down-regulation of 5-HT2A receptors. Electroencephalography, a non-invasive neuroimaging tool, can track the acute effects of psilocybin; these include the suppression of alpha activity, decreased global connectivity, and increased brain entropy (i.e. brain signal diversity) in eyes-closed resting-state. However, few studies investigated how these modalities are affected together through the psychedelic experience. The current research aimed to evaluate the psilocybin intoxication temporal EEG profile. 20 healthy individuals (10 women) underwent oral administration of psilocybin (0.26 mg/kg ) as part of a placebo-controlled cross-over study, resting-state 5-minute eyes closed EEG was obtained at baseline and 1, 1.5, 3, 6, and 24 hours after psilocybin administration. Absolute power, relative power spectral density (PSD), power envelope global functional connectivity (GFC), Lempel-Ziv complexity (LZ), and a Complexity via State-Space Entropy Rate (CSER) were obtained together with measures of subjective intensity of experience. Absolute power decreased in alpha and beta band, but increased in delta and gamma frequencies. 24h later was observed a broadband decrease. The PSD showed a decrease in alpha occipitally between 1 and 3 hours and a decrease in beta frontally at 3 hours, but power spectra distribution stayed the same 24h later. The GFC showed decrease acutely at 1, 1.5, and 3 hours in the alpha band. LZ and showed an increase at 1 and 1.5 hours. Decomposition of CSER into functional bands shows a decrease in alpha band but increase over higher frequencies. Further, complexity over a source space showed opposing changes in the Default Mode Network (DMN) and visual network between conditions, suggesting a relationship between signal complexity, stimulus integration, and perception of self. In an exploratory attempt, we found that a change in gamma GFC in DMN correlates with oceanic boundlessness. Psychological effects of psilocybin may be wrapped in personal interpretations and history unrelated to underlying neurobiological changes, but changes to perception of self may be bound to perceived loss of boundary based on whole brain synchrony with the DMN in higher frequency bands.

BackgroundA common feature of Cannabis use disorder (CUD) is an intense reactivity to cannabis cues, which are becoming increasingly visible due to growth in the decriminalization, accessibility and marketing of cannabis products. The brains automatic reactivity to cannabis cues can trigger craving and subsequent use. This study aimed to test neural activity during cannabis cue-induced craving in non-treatment seeking individuals with moderate-to-severe CUD, with past attempts to cut down/quit. MethodsThe study examined 65 individuals with moderate-to-severe CUD and 43 controls, with a fMRI cannabis cue-induced craving task and assessment of mental health, substance use, and cognitive testing. Group differences in neural cue-induced craving were examined, adjusting for age and sex; correlations with cannabis use characteristics were assessed, accounting for recent substance use. ResultsIndividuals with a CUD relative to controls showed greater brain activity during cannabis cue-induced craving in the superior/middle occipital, medial/lateral OFC, anterior/posterior cingulate, cerebellar, hippocampus, middle temporal and lateral parietal cortices (p < .05; cluster k > 10, FWE-corrected). Greater occipital/cerebellar activity correlated with greater subjective arousal towards cannabis images and cannabis withdrawal scores, while anterior cingulate/inferior parietal activity negatively correlated with urinary level of 11-Nor-9-carboxy-{Delta}9-tetrahydrocannabinol:creatinine (ps<.05). ConclusionsExposure to cannabis cues can elicit greater activity within salience evaluation/attention, motivation and disinhibition pathways of addiction neurocircuitry in people with moderate-to-severe CUD, consistent with prominent neuroscientific theories of addiction and findings with other substances. Interventions which can suppress brain activity in salience and attention circuits during cannabis-induced craving may help reduce craving and subsequent use.

Cannabis use disorder (CUD) affects [~]22M people globally and is characterised by difficulties in cutting down and quitting use, but the underlying neurobiology remains unclear. We examined resting-state functional connectivity (rsFC) between regions-of-interest (ROIs) of the addiction neurocircuitry and the rest of the brain in 65 individuals with moderate-to-severe CUD who reported attempts to cut down or quit, compared to 42 controls, and explored the association between rsFC and cannabis exposure and related problems, to elucidate potential drivers of rsFC alterations. The CUD group showed greater rsFC than controls between ROIs implicated in reward processing and habitual substance use (i.e., nucleus accumbens, putamen, pallidum) and occipito/parietal areas implicated in salience processing and disinhibition. Putamen-occipital rsFC correlated with levels of problematic cannabis use and depression symptoms. CUD appears to show neuroadaptations of the addiction neurocircuitry, previously demonstrated in other substance use disorders.

ObjectivesCombined oral contraceptive (COC) use is linked to increased depression risk, potentially via serotonergic pathways. This study examined whether serotonin 2A/2C receptor (5-HT2AR/5-HT2CR) brain binding differs between healthy women using COCs and non-users. Methods71 healthy women had been scanned with either [18F]Altanserin (17 COC users, 22 non-users) or [11C]Cimbi-36 Positron Emission Tomography (17 COC users, 15 non-users). Multiple linear regression and latent variable models were used to assess associations between COC use and neocortical 5-HT2AR and subcortical-HT2AR/5-HT2CR binding, respectively.. Analyses were performed on data pooled across both radiotracers and on each tracer, separately. ResultsIn pooled analyses across both tracers, COC use was not significantly associated with 5-HT2AR binding in the neocortex (-7.7%, 95% CI [-18.9;5.2], p=0.22), nor with 5-HT2AR/5-HT2CR in subcortical regions (-7.8, 95% CI [-21.7;7.7], p=0.31). In [11C]Cimbi-36-only analyses, COC use was associated with -12.6% (95% CI [-22.1;-1.9], p=0.02) lower 5-HT2AR binding in neocortex and -23.5% lower 5-HT2AR/5-HT2CR binding in subcortical regions (95% CI [-35.6;-9.1], p=0.002). No significant differences were observed in the [18F]Altanserin-only analyses. ConclusionThe [11C]Cimbi-36 data indicated lower cortical 5-HT2AR and subcortical 5-HT2AR/5-HT2CR binding in COC users compared to non-users, but this was not observed in the [18F]Altanserin data. This may reflect better signal-to-noise properties of [11C]Cimbi-36 and the fact that it binds more selectively to the high-affinity, biologically active receptor state. These results offer potential mechanistic insights into the depression risk associated with COC use and may have implications for treatments targeting 5-HT2AR/5-HT2CR, underscoring the need for replication and further investigation. Highlights1) COC use was associated with lower 5-HT2AR/CR brain binding in Cimbi-36 PET data 2) COC use was not associated with 5-HT2AR brain binding in [18F]Altanserin PET data 3) We speculate if lower 5-HT2AR/CR levels may affect treatments targeting 5-HT2AR/CR

BackgroundMirtazapine is contraindicated for individuals under 18 by the Swedish Medical Products Agency (Lakemedelsverket), yet recent data reveals its increasing off-label prescription to adolescents for insomnia and anxiety symptoms. This practice occurs despite established safety concerns and contradicts the drugs approved indication for major depressive disorder requiring 30-45 mg/day. MethodsWe analyzed nationwide prescription data from 2007-2017 using CSV files from Swedish, Danish, and Norwegian registries, complemented by a mini systematic review of 42 peer-reviewed studies. Dose-response relationships, discontinuation rates, and adverse event profiles were examined. ResultsSwedish adolescents received mirtazapine at a mean dose of 8.84-10.76 mg/day (95% CI), significantly below the therapeutic range for depression but optimal for sedation [3, 11, 22]. This pattern contrasts with Nordic neighbors, with Sweden demonstrating 184.1% higher mirtazapine prescription rates for 15-19-year-olds compared to Denmark (6.05% vs. 2.99% of total prescriptions). The practice represents a deliberate clinical strategy within Swedens centralized healthcare system, where specialists use mirtazapine as a benzodiazepine alternative under "therapeutic freedom" [6, 28]. Critically, this off-label use exposes adolescents to significant risks including weight-independent metabolic damage (2.8-fold higher prediabetes incidence) [16, 24], movement disorders [17, 29], and rebound insomnia with 57.3% discontinuation rates driven by anxiety/agitation rather than metabolic side effects [21, 30]. ConclusionMirtazapines off-label use in Swedish adolescents represents a concerning therapeutic paradox: while increasing nighttime sleep by approximately 30 minutes [4, 45], it simultaneously induces daytime sleepiness and cognitive impairment [7, 46], directly undermining the primary goal of insomnia treatment. The evidence demonstrates an intentional clinical practice rather than prescribing error, highlighting a critical regulatory gap that requires immediate attention. Policy interventions should include revised prescribing guidelines with mandatory monitoring protocols for adolescents receiving mirtazapine, alongside public health campaigns to address the growing off-label use of antidepressants for sleep disorders.

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

At least 60% of individuals with anxiety disorders report sleep disturbances. Shared physiological mechanisms might explain their co-occurrence. Scientific literature related to medical cannabis, a promising therapeutical candidate for these conditions, increased about 15 times in the last 10 years. However, assessments of cannabinoid exposure, anxiety, and sleep are inconsistent across studies, and the quality of the evidence is not often evaluated. We developed a Scoping Review to examine the current knowledge on these gaps related to cannabinoid use for anxiety and sleep disturbances. This protocol provides detailed information on how the scoping review will be conducted. It shows the inclusion criteria for studies on the topic of interest as well as the search strategies for the following databases: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, LILACS, and PsycINFO. We present the methodological aspects for screening, data extraction, and data charting. In addition, we proposed to evaluate the quality of the evidence by applying critical appraisal tools according to the study designs. Adherence to this protocol will allow the research team to effectively and reliably synthesize research evidence on the effect of cannabinoids on anxiety symptoms and sleep disturbances.

BackgroundBehavioural studies in animal models represent a critical component of psychiatric drug development. Positive results in animal studies have identified novel therapeutic targets for major depressive disorder (MDD) but efficacy in humans has largely not been borne out in clinical trials. A possible reason for this failed translation is inappropriate dose selection and the engagement of mechanisms not directly relevant to antidepressant effects in patients. MethodsWe first used PubMed to identify preclinical rodent studies in two assays used to assess antidepressants; the conventional forced swim test, (FST) and more recently developed affective bias test, (ABT). Dose ranges were extracted, as well as information about subjects, timing and route of administration, and justification and efficacy of dose(s). Dose ranges were compared against calculated animal equivalent doses. ResultsThe median FST dose across all antidepressants was 10mg/kg, with median doses for each drug exceeding the relevant animal equivalent dose by 1.5-25x. In contrast, effective doses in the ABT showed closer alignment to those used clinically. In the second study, 232 ketamine and 202 fluoxetine papers involving MDD-related research in rodents were reviewed. The median dose was 10mg/kg for both drugs, exceeding animal equivalent doses by 1.6-3.2x and 3.2-6.5x for ketamine and fluoxetine, respectively. ConclusionsThe results indicate pervasive use of antidepressant doses in conventional models of MDD that may not correspond with doses used in clinical practice. We discuss the implications of using doses which exceed therapeutic levels and the potential to engage receptors and underlying mechanisms which are not relevant to clinical effects.

Adults aged [&ge;]65 years are increasingly using cannabis products. However, controlled pharmacokinetic and pharmacodynamic data on {Delta}9-tetrahydrocannabinol (THC) in this population are sparse, and remain limited to oral/oromucosal formulations. To characterize the acute pharmacokinetic and pharmacodynamic effects of oral and vaporized THC in healthy adults aged [&ge;]65, we conducted a two-arm, randomized, double-blind, placebo-controlled trial in which 20 participants (mean age 70.0, SD: 5.1 years) received oral (placebo, 5 mg, or 10 mg) or vaporized THC (placebo, 2 mg, or 4 mg) across three eight-hour sessions separated by [&ge;]72 hours. Outcomes included plasma pharmacokinetics, subjective drug effects, reinforcement value, cognitive performance, heart rate (HR), blood pressure (BP), and adverse events (AEs). Oral THC was associated with delayed, lower THC exposure (Tmax 60-90 min; Cmax 2.6-6.2 ng/mL), with 11-OH-THC concentrations approximately matching parent-THC; slow-rising subjective effects; no change in reinforcement value; no significant change in HR or BP; and no AEs. Vaporized THC was associated with rapid, THC-dominant exposure (Tmax 3 min; Cmax 24.6-53.8 ng/mL) and minimal 11-OH-THC concentrations; rapid-onset subjective effects; increased reinforcement value at 4 mg; and significant HR elevation peaking within 5 min, without significant BP change. Cognitive performance did not differ from placebo at any oral or vaporized THC dose. At vaporized THC 4 mg, two participants experienced five AEs. Oral and vaporized THC produce route-specific pharmacokinetic and pharmacodynamic profiles in adults aged [&ge;]65, including an increase in reinforcement value only after vaporization, and should therefore not be treated as interchangeable in risk assessment for older adults.

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.

The brain age gap (BAG) -- the difference between chronological and neuroimaging-based predicted brain age -- has emerged as a sensitive biomarker of brain health. A higher BAG, reflecting an older-appearing brain, has been linked to cognitive decline, neurodegenerative disease, and mental disorders. Whether such apparent aging can be mitigated by targeted interventions remains unclear. Oestradiol (E2), a sex hormone fluctuating across the menstrual cycle and known for its neuromodulatory and cognitive effects, may represent one such target intervention. To test this, we conducted a double-blind, randomized, placebo-controlled crossover study in 28 premenopausal females. Each participant was assessed twice during the follicular phase, with at least two cycles between sessions, and received either 12 mg E2-valerate or a placebo before undergoing a T1-weighted MRI scan. BAG was estimated using a pre-trained Simple Fully Convolutional Network model. Predicted brain age was significantly younger following E2 administration compared to placebo. Exploratory analyses indicated that this effect may be moderated by resilience factors for mental health: Higher self-esteem and use of greater social support seeking was nominally associated with lower BAG, whereas females applying more expressive suppression showed more apparent brain aging. These findings suggest that even short-term increases in E2, together with resilience factors, can influence brain age estimates. Thus, E2 interventions may provide a targeted approach to support both brain and mental health. These findings underscore the urgent need for further research into the impact of E2 on mental health across the female lifespan.

This international online study (N=759) examined the acute, subacute, and long-term effects of psychedelic drug use on cognitive performance and mental health. Participants completed cognitive tasks assessing working memory, selective attention, and visual/spatial perception, as well as questionnaires assessing mental health outcomes and quality of life. Based on self-reported substance use, participants were classified as non-users, lifetime users, and recent users. Recent users had significantly lower accuracy across all cognitive tasks, and lifetime users had the highest task accuracy without corresponding reaction time deficits. Lifetime use was not associated with long-term cognitive decline. Recent users reported more depressive and dissociative symptoms, whereas lifetime users reported lower scores. Lifetime users scored lower on psychological and social quality of life domains, indicating possible long-term psychosocial effects. These findings highlight the need to differentiate between the acute and long-term effects of psychedelics; lab-controlled, longitudinal studies are needed to enable safe clinical application.

IntroductionThe primary psychoactive component in marijuana is tetrahydrocannabinol (THC), which acts on receptors, such as cannabinoid 1 (CB1), that are distributed broadly throughout the brain. THC interferes with synaptic plasticity and neurogenesis and impacts the brains macrostructure, specifically white matter where CB1 receptors are abundant. The current study aims to investigate whether callosal morphology differs depending on how much experience individuals have with marijuana. MethodsThis is a quantitative between-group corpus callosum morphology analysis using cohort study data. The data for this study (n = 144) came from the S1200 Release from the Washington University - University of Minnesota Human Connectome Project Consortium (WU-Minn HCP). Marijuana use was quantified using self-reports and grouped as (1) no use, (2) low use, and (3) high use. T1-weighted MRI brain images were obtained and then processed using SPM12 and MATLAB. Each corpus callosum was manually traced and automatically separated into seven callosal areas according to the Witelson parcellation scheme. The resulting area measures were compared between the three groups, while covarying for total brain volume. ResultsOur ANCOVA analysis was significant (F(2, 145) = 4.38, p = .014), and posthoc tests revealed a significantly smaller anterior midbody in the high marijuana use group compared to the no marijuana use group (p = .012). ConclusionSmaller callosal areas in the high use marijuana group suggest that heavy cannabis may be related to weaker interhemispheric connectivity. Future research is required to replicate the current findings using well-powered designs.

BackgroundGamma-hydroxybutyric acid (GHB) use disorder (GUD) is well known for its severe withdrawal syndrome. Currently, tapering with pharmaceutical GHB is the preferred option to mitigate withdrawal. The gamma-aminobutyric acid (GABA)-B receptor agonist baclofen could improve GHB detoxification, due to its longer half-life than pharmaceutical GHB and specific GABA-B receptor activation. However, clinical data on baclofens effectiveness to manage GHB withdrawal is limited. We aim to explore potential benefits of baclofen as an add-on to pharmaceutical GHB tapering in patients with GUD. MethodsThis prospective, non-randomized, clinical trial consists of two phases: 1) a proof-of-concept phase (n=10) and 2) a dose-finding phase (n= 18). Primary objective of the proof-of-concept phase is to assess whether baclofen add-on therapy reduces the need for pharmaceutical GHB during inpatient detoxification. Safety and feasibility will also be assessed. Aim of the dose-finding phase is to explore the optimal baclofen dosage when used as add-on therapy during inpatient GHB detoxification. Criteria to start the second phase are that baclofen add-on therapy leads to a dose reduction of pharmaceutical GHB without severe side effects. GHB withdrawal symptoms and baclofen side effects will be monitored during GHB detoxification, using questionnaires. DiscussionWe expect that baclofen add-on therapy will reduce the need for pharmaceutical GHB during inpatient GHB detoxification. This will likely result in a less intensive detoxification process for patients and will improve the overall feasibility of GHB detoxification. If the outcome of the current phase II trial is positive, either a replication phase II trial with a randomized blinded design or a lager phase III trial, would be a logical follow-up study to confirm the safety, feasibility and efficacy of baclofen add-on therapy during inpatient GHB detoxification. Trial registrationThis study protocol is approved by the Medical Ethical Research Committee Oost-Nederland and Central Committee on Research Involving Human Subjects. The study is registered in the Clinical Trial Information System under EU CT-number: 2023-506167-34-02.

This Phase I trial aims to inform the development of safety protocols for psilocybin-assisted therapy. Psychedelics, including psilocybin, are increasingly being recognized as a successful treatment option for many mental health concerns. In order to decrease the risks associated with its clinical use, more data is required regarding its physiological effects in healthy individuals. Safety assessments (heart rate, blood pressure, temperature, and ECG data), as well as adverse event evaluations were the primary outcome measures used to assess the physiological effects of 25 mg of psilocybin extract administered to 14 healthy individuals. We hypothesized that there would be a transient, clinically insignificant rise in both blood pressure and heart rate that would not result in any long-term adverse effects. No unexpected effects were observed, blood pressure and heart rate returned to normal as drug effects waned, and all participants had normal two-month follow-ups. Mean peak systolic and diastolic blood pressures during the psilocybin session were 145.93 (SD = 19.01) and 93.93 (SD = 9.75), respectively. While this represents a significant increase from baseline (p < 0.0001), a healthy cardiovascular system is capable of tolerating such levels for a longer time period than the brief duration of drug effects. Therefore, we suggest implementing focused and limited screening protocols to balance patient safety and accessibility. Secondary outcomes of this trial centered on the subjective effects of psilocybin, assessed via the QIDS-SR16 and the MEQ-30. There was a statistically significant decrease in QIDS-SR16 scores from baseline scores (M = 3.50, SD = 2.35) to eight-week follow-up scores (M = 1.86, SD = 0.86), p = 0.018. Mean MEQ-30 scores, assessed on day two and seven after the psilocybin session, indicate participants had full mystical experiences.

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.

Study ObjectivesThis study investigated the associations between prenatal alcohol exposure (PAE), including low and moderate levels of exposure, and sleep outcomes in adolescence. This is an area that remains understudied despite evidence linking PAE to poor sleep in younger children and the growing recognition of harms associated with low levels of PAE. MethodsParticipants were 10,336 adolescents (aged 12-13) from the fourth assessment wave of the Adolescent Brain Cognitive Development Study. Cross-sectional generalised linear mixed models and generalised additive mixed models were used to assess the impact of prenatal alcohol exposure, conceptualised as the presence and absence of PAE, total drinks consumed during pregnancy (i.e. dose), and patterns of PAE (i.e., abstainers, light reducing, light stable, heavy reducing), on adolescent sleep outcomes. ResultsAdolescents with any PAE experienced worse sleep outcomes compared to those without, with the sleep-wake transitions and excessive somnolence being the domains most impacted. A non-linear dose effect was observed, whereby worse sleep-wake transitions occurred predominantly with low levels of exposure. In addition, those in the group with a light reducing pattern of PAE, compared to abstainers, experienced greater problems with sleep-wake transitions. ConclusionThese findings contribute to the growing evidence that there are no safe levels of alcohol consumption during pregnancy, as even low to moderate PAE negatively impacts adolescent sleep. Identifying sleep-wake transitions and excessive somnolence as the most affected domains provides targets for both screening and intervention.

BackgroundQuetiapine is an antipsychotic drug with unique pharmacological properties approved for the treatment of schizophrenia, bipolar disorder, and augmentation for major depressive disorder. In routine clinical practice, it is also frequently prescribed for conditions such as insomnia, anxiety, and psychomotor agitation. Italfarmaco (ITF) Group has developed an innovative oral suspension formulation of quetiapine; its composition, optimized in viscosity and stability, aims to facilitate administration and dosing across a wide range of patient profiles, particularly those requiring low doses or those with difficulty swallowing, limited manual dexterity, or cognitive impairment. ObjectiveThis study aimed to evaluate the pharmacokinetic (PK) profile of this innovative oral suspension formulation of quetiapine compared to the immediate-release tablets. MethodsA single-dose, open-label, randomized, two-sequence, two-treatment, two-period cross-over pivotal study was conducted in 43 healthy subjects under fasting conditions. Volunteers received a single 25 mg dose of quetiapine, administered either as an oral suspension or as an immediate-release film-coated tablet, with an appropriate washout between treatments. The PK performance of the two formulations was compared, maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under the curve (AUC), and overall bioavailability. Plasmatic quetiapine levels were measured by validated high performance liquid chromatography (HPLC) methods blinded to the dosing randomization scheme. ResultsQuetiapine oral suspension demonstrated pharmacokinetic bioequivalence to the reference tablet in terms of Cmax and AUC. It exhibited faster absorption, being detectable in plasma within 10 minutes following oral administration, with a median tmax of 0.75 h compared to 1.02 h for the immediate-release tablet. Calculating the median tmax difference for each subject shows that quetiapine oral suspension reaches peak plasma concentration about 30 minutes faster than the immediate-release tablet. ConclusionThis novel quetiapine oral suspension formulation addresses key unmet needs in psychiatric pharmacotherapy treatment by combining a favorable pharmacokinetic profile with a patient-centered design. It enables precise dose titration of the drug and promotes faster absorption, thereby potentially achieving a more rapid onset of action. This formulation facilitates administration and dosing flexibility, an advantage for all patients, especially for the ones requiring low doses. KEY POINTSO_LIItalfarmaco (ITF) has developed an innovative oral suspension formulation of quetiapine. C_LIO_LIThis novel quetiapine oral suspension formulation enables precise dose titration of the drug and promotes faster absorption, thereby potentially achieving a more rapid onset of action. C_LIO_LIITF quetiapine suspension formulation is intended to address key unmet needs in antipsychotic pharmacotherapy treatment by combining a favorable pharmacokinetic profile with a patient-centered design. C_LI

BackgroundSleep is a fundamental determinant of health, yet little is known about sleep in carceral environments where structural, environmental, and psychosocial factors uniquely disrupt rest. Incarcerated individuals face disproportionately high burdens of illness, with sleep disturbances contributing to these disparities. Understanding the evidence on sleep in incarceration is essential for informing care, policy, and research. MethodsWe conducted a scoping review of peer-reviewed literature on sleep in incarcerated populations, following the Joanna Briggs Institute Manual and PRISMA-ScR guidelines. Ten databases were searched from inception to March 2025 for studies addressing sleep among currently incarcerated individuals. Two reviewers screened and extracted data, with quality appraisal adapted from Joanna Briggs Institute tools. ResultsOf 5,518 records identified, 63 studies published between 1978 and 2025 met inclusion criteria. Most were observational (75%), cross-sectional (59%), and published after 2014, with studies conducted mostly outside the United States. Research clustered into three domains: (1) descriptions of sleep quality and insomnia; (2) sleep and health outcomes, particularly depression, anxiety, PTSD, aggression, and suicidality, with limited study of cardiometabolic risk; and (3) interventions including cognitive behavioral therapy for insomnia, mindfulness, yoga, and relaxation, which showed feasibility but were limited by small samples, lack of controls, or short follow-up. Objective measures were rarely used. ConclusionsEvidence demonstrates compromised sleep health in carceral settings due to psychiatric comorbidity, environmental stressors, and restricted care. Gaps remain in physical health outcomes, womens experiences, and post-release effects. Interventions tailored to carceral realities and adapted evidence-based interventions showed promise.

BackgroundThe prescription of psychotropic medication is rising in Europe along the last decade. Exploring consumption patterns in pre-pandemic times in Portugal, as well as relevant socio-demographic determinants, can help establish comparisons with worldwide patterns and support public health policies for mental health. MethodsDescriptive, non-comparative cohort study, comprising full nationwide drug prescription records in Portugal along antidepressant, antipsychotic, and anxiolytic classes. Statistical analysis of prescription and consumption patterns according to reference dosages and guided by several criteria, including active substance, demographics, geography, associated medical specialty, and incurred costs. ResultsAn increase of 29.6% and 34.7% in the consumption of antipsychotics and antidepressants between 2016 and 2019 is highlighted, reasonably accompanied by an increase of 37M Eur in total expenditure (>20M Eur in public copay) for these classes of drugs. Disparities in sociodemographic and geographical incidence are identified. Amongst other pivotal results, we further observed that 64% of psychotropic drug prescriptions are undertaken by general practitioners, while only 21% undertaken by neurological and psychiatric specialties. ConclusionNationwide patterns of psychotropic drug prescription in Portugal reveal notable trends and determinants, establishing a reference point for cross-regional studies and being currently assessed at a national level to establish psychosocial initiatives and guidelines for the clinical practice and medical training. NoveltyTo our knowledge, first Portuguese psychopharmacoepidemiological study assessing: 1) economic correlates; 2) prescription patterns by medical specialty; 3) adherence rates and geographical determinants; 4) consumption patterns by active substance; and 5) systematic trends for the pre-pandemic period.