Journal of Psychopharmacology

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

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.

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.

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.

Abstract Background Insomnia is a major public health problem affecting an estimated 852 million adults worldwide. Current pharmacological treatments, including benzodiazepines and Z-drugs, carry serious risks of dependency, cognitive impairment, and adverse events. These limitations have driven growing interest in complementary and alternative therapies, particularly herbal sedatives, which are perceived as natural and safer. However, evidence on their safety and efficacy remains insufficient and patchy. Objective: This review evaluated the effectiveness of lesser known herbal sedatives for insomnia. Methods The protocol was registered with PROSPERO (CRD420251101795). Eligibility was defined using the PICO framework: Population: adults aged [&ge;]18 years with insomnia; Interventions: Passiflora incarnata, Hawthorn, Melissa officinalis, Chamomile, Viola odorata, Nelumbo nucifera, Rhodiola rosea, and Eschscholtzia californica. Comparators: placebo or usual care; Primary and Secondary Outcomes: sleep quality (Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale), sleep duration, and sleep latency. Databases and registers were searched from January 2005 to July 2025. Randomized controlled trials, nonrandomized controlled trials, clinical trials, and observational studies were included. Five reviewers independently screened studies. Data extraction used a structured Excel spreadsheet. Risk of bias was assessed using RoB 2.0 for randomized trials and ROBINS-I V2 for nonrandomized studies. Random-effects meta-analyses (DerSimonian and Laird) were conducted in RevMan. Narrative synthesis followed SWiM guidelines. Results From 1,294 records, 32 studies met eligibility criteria. Meta-analysis of 23 RCTs demonstrated a statistically significant pooled effect favouring herbal sedatives (SMD -0.77, 95% CI -1.14 to -0.40, p=0.0001), with substantial heterogeneity (I square=92%). Subgroup analysis showed larger effects for chamomile (SMD -1.06) and Melissa officinalis (SMD -0.66). Most RCTs had high overall risk of bias; nonrandomized studies predominantly had critical risk of bias. Conclusions This systematic review provides preliminary evidence that several herbal sedatives, particularly chamomile and Melissa officinalis, may improve insomnia-related outcomes. However, methodological weaknesses, high risk of bias, and substantial heterogeneity limit evidence strength. Future research requires standardized extracts, large multicentre RCTs, and extended follow-up.

Background and AimsCannabis is the most widely used illicit drug worldwide and is often co-used with tobacco, the leading cause of preventable death. Although cannabis and tobacco have distinct neurobiological actions, their associations with brain volumes are unclear. We aimed to systematically review brain volumes associated with cannabis use, tobacco use, and their co-use. DesignSystematic review and meta-analysis (CRD42022356982). SettingSCOPUS, PubMed and PsycINFO were searched up to 5 September 2024 ParticipantsSearches yielded 103 studies: 57 investigated cannabis use, 45 investigated tobacco use, and one investigated tobacco and cannabis co-use. MeasurementsWe extracted adjusted and unadjusted estimates. Random effects meta-analyses were stratified by exposure and study design across 33 brain regions. Risk of bias was assessed using a modified version of the Newcastle-Ottawa scale. FindingsMeta-analysis of adjusted estimates from cross-sectional studies indicated smaller amygdala volumes (k = 17, g = 0.13, 95%CI [0.03, 0.23]) in people who use cannabis compared to controls. Relative to controls, people who smoked tobacco had smaller volumes in the amygdala (k = 5, g = 0.17, 95%CI [0.04, 0.31]), insula (k = 5, g = 0.17, 95%CI [0.06, 0.27]), pallidum (k = 5, g = 0.17, 95%CI [0.13, 0.21]) and total grey matter volume (TGMV) (k = 7, g = 0.17, 95%CI [0.04, 0.30]). Longitudinal studies indicated a larger decrease in TGMV in people who smoke tobacco (k = 5, g = 0.05, 95%CI [0.01, 0.10]) relative to controls. ConclusionsThere was evidence that cannabis use was associated with smaller volume in the amygdala. Tobacco use was associated with smaller amygdala, insula, pallidum and total grey matter volume.

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.

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

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.

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.

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

Structured AbstractO_ST_ABSImportanceC_ST_ABSKetamine has well known dissociative, analgesic, and antidepressant properties, but it is unknown whether the neurophysiologic effects that are associated with these properties can be modulated separately from one another. Given prior studies that link specific cortical oscillations with specific therapeutic effects, it is likely that modulating selective aspects of ketamine neurophysiology can inform efforts to develop more targeted therapies. ObjectiveTo determine how the neurophysiologic signatures of ketamine are influenced by removal of conscious awareness using general anesthesia. DesignObservational cohort study from trials spanning 2017 to 2023. SettingMulticenter study using data from two study cohorts (U-Michigan and Stanford) and supplementary analysis of a third cohort (U-Auckland). Participants52 participants in primary analysis and 27 additional participants in supplementary analyses. Study cohorts included healthy volunteers, patients undergoing elective surgery, and patients with a diagnosis of depression. InterventionParticipants received a subanesthetic infusion of ketamine (0.5 mg/kg) or placebo with or without general anesthesia (GA). Main Outcome and MeasureChanges in electroencephalographic (EEG) band power during medication infusion. ResultsGA differentially alters EEG features commonly associated with ketamine. In comparison to awake administration, ketamine during GA preserves its high-frequency power modulation but lacks its characteristic low-frequency augmentation. Conclusions and RelevanceCo-administration of ketamine with GA selectively modulates the high- and low-frequency neurophysiological correlates of ketamine, suggesting a method to explore these components role in ketamines behavioral effects.

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.

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.

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

Insomnia is a common sleep disorder, and many individuals seek alternative treatments like homeopathy. However, evidence for its effectiveness remains controversial. This systematic review and meta-analysis evaluated the effectiveness of homeopathic interventions for insomnia and sleep-wake disorders. A comprehensive search of PubMed, MEDLINE, CINAHL, and the Cochrane Library was conducted for studies published between 2010 and 2025. We included randomized controlled trials (RCTs) and non-randomized studies involving adults ([&ge;]18 years) with primary insomnia receiving any homeopathic intervention compared to placebo, no treatment, or active care. Primary outcomes included validated sleep quality measures (e.g., Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI). Four reviewers independently performed study selection, data extraction, and risk of bias assessment using RoB 2.0 and ROBINS-I. A random-effects meta-analysis was conducted for controlled trials, and a narrative synthesis for non-randomized studies. Certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE). The search yielded 1304 records; 12 studies (nine RCTs and three non-randomized) met inclusion criteria. Meta-analysis showed a large, statistically significant positive effect of homeopathy on sleep outcomes (SMD = 0.81, 95% CI [0.24, 1.38], p = 0.0055), with substantial heterogeneity (I{superscript 2} = 86.04%) and publication bias (Eggers test, p = 0.0079). Most studies had high or critical risk of bias, and overall certainty was low. Homeopathic interventions showed a large positive effect on sleep outcomes, but due to high bias, heterogeneity, and publication bias, evidence remains low-certainty and insufficient to support effectiveness. High-quality RCTs are needed. Systematic Review RegistrationPROSPERO CRD42025649926.

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.

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.