Dose-dependent effects of oral cannabidiol and delta-9-tetrahydrocannabinol on serum anandamide and related N-acylethanolamines in healthy volunteers.

BACKGROUND: The mental health benefits of cannabidiol (CBD) are promising but can be inconsistent, in part due to challenges in defining an individual's effective dosage. In schizophrenia, alterations in anandamide (AEA) concentrations, an endocannabinoid (eCB) agonist of the eCB system, reflect positively on treatment with CBD. Here, we expanded this assessment to include eCBs alongside AEA congeners, comparing phytocannabinoids and dosage in a clinical setting. METHODS: Liquid chromatography-tandem mass spectrometry quantified changes in serum levels of AEA, 2-arachidonoylglycerol (2-AG), alongside AEA-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which were attained from two independent, parallel-designed, clinical trials investigating single, oral CBD (600 or 800 mg), delta-9-tetrahydrocannabinol (Δ9-THC, 10 or 20 mg) and combination administration (CBD|800 mg+Δ9-THC|20 mg) in healthy volunteers (HVs, n=75). Concentrations were measured at baseline (t=0), 65 and 160 min post administration. RESULTS: CBD-led increases in AEA (1.6-fold), OEA and PEA (1.4-fold) were observed following a single 800 mg (pcorr<0.05) but not 600 mg dosage. Declining AEA was observed with Δ9-THC at 10 mg (-1.3-fold) and 20 mg (-1.4-fold) but restored to baseline levels by 160 min. CBD+Δ9-THC yielded the highest increases in AEA (2.1-fold), OEA (1.9-fold) and PEA (1.8-fold) without reaching a maximal response. CONCLUSION: CBD-administered effects towards AEA, OEA and PEA are consistent with phase II trials reporting clinical improvement for acute schizophrenia (CBD≥800 mg). Including Δ9-THC appears to enhance the CBD-induced response towards AEA and its congeners. Our results warrant further investigations into the potential of these lipid-derived mediators as metabolic measures for CBD dose prescription and co-cannabinoid administration.

Alterations to sphingolipid metabolism from antipsychotic administration in healthy volunteers are restored following the use of cannabidiol.

Randomized clinical trials substantiate cannabidiol (CBD) as a next-generation antipsychotic, effective in alleviating positive and negative symptoms associated with psychosis, while minimising the adverse effects seen with established treatments. Although the mechanisms remain debated, CBD is known to induce drug-responsive changes in lipid-based retrograde neurotransmitters. Lipid aberrations are also frequently observed with antipsychotics, which may contribute to their efficacy or increase the risk of undesirables, including metabolic dysfunction, obesity and dyslipidaemia. Our study investigated CBD's impact following lipid responses triggered by interaction with second-generation antipsychotics (SGA) in a randomized phase I safety study. Untargeted mass spectrometry assessed the lipidomic profiles of human sera, collected from 38 healthy volunteers. Serum samples were obtained prior to commencement of any medication (t = 0), 3 days after consecutive administration of one of the five, placebo-controlled, treatment arms designed to achieve steady-state concentrations of each SGA (amisulpride, 150 mg/day; quetiapine, 300 mg/day; olanzapine 10 mg/day; risperidone, 3 mg/day), and after six successive days of SGA treatment combined with CBD (800 mg/day). Receiver operating characteristics (ROC) refined 3712 features to a putative list of 15 lipids significantly altered (AUC > 0.7), classified into sphingolipids (53 %), glycerolipids (27 %) and glycerophospholipids (20 %). Targeted mass spectrometry confirmed reduced sphingomyelin and ceramide levels with antipsychotics, which mapped along their catabolic pathway and were restored by CBD. These sphingolipids inversely correlated with body weight after olanzapine, quetiapine, and risperidone treatment, where CBD appears to have arrested or attenuated these effects. Herein, we propose CBD may alleviate aberrant sphingolipid metabolism and that further investigation into sphingolipids as markers for monitoring side effects of SGAs and efficacy of CBD is warranted.

ReTimeML: a retention time predictor that supports the LC-MS/MS analysis of sphingolipids.

The analysis of ceramide (Cer) and sphingomyelin (SM) lipid species using liquid chromatography-tandem mass spectrometry (LC-MS/MS) continues to present challenges as their precursor mass and fragmentation can correspond to multiple molecular arrangements. To address this constraint, we developed ReTimeML, a freeware that automates the expected retention times (RTs) for Cer and SM lipid profiles from complex chromatograms. ReTimeML works on the principle that LC-MS/MS experiments have pre-determined RTs from internal standards, calibrators or quality controls used throughout the analysis. Employed as reference RTs, ReTimeML subsequently extrapolates the RTs of unknowns using its machine-learned regression library of mass-to-charge (m/z) versus RT profiles, which does not require model retraining for adaptability on different LC-MS/MS pipelines. We validated ReTimeML RT estimations for various Cer and SM structures across different biologicals, tissues and LC-MS/MS setups, exhibiting a mean variance between 0.23 and 2.43% compared to user annotations. ReTimeML also aided the disambiguation of SM identities from isobar distributions in paired serum-cerebrospinal fluid from healthy volunteers, allowing us to identify a series of non-canonical SMs associated between the two biofluids comprised of a polyunsaturated structure that confers increased stability against catabolic clearance.

Cannabidiol and its Potential Evidence-Based Psychiatric Benefits - A Critical Review.

The endocannabinoid system shows promise as a novel target for treating psychiatric conditions. Cannabidiol (CBD), a naturally occurring cannabinoid, has been investigated in several psychiatric conditions, with diverse effects and an excellent safety profile compared to standard treatments. Even though the body of evidence from randomised clinical trials is growing, it remains relatively limited in most indications. This review comprises a comprehensive literature search to identify clinical studies on the effects of CBD in psychiatric conditions. The literature search included case studies, case reports, observational studies, and RCTs published in English before July 27, 2023, excluding studies involving nabiximols or cannabis extracts containing CBD and ∆9-tetrahydrocannabinol. Completed studies were considered, and all authors independently assessed relevant publications.Of the 150 articles identified, 54 publications were included, covering the effects of CBD on healthy subjects and various psychiatric conditions, such as schizophrenia, substance use disorders (SUDs), anxiety, post-traumatic stress disorder (PTSD), and autism spectrum disorders. No clinical studies have been published for other potential indications, such as alcohol use disorder, borderline personality disorder, depression, dementia, and attention-deficit/hyperactivity disorder. This critical review highlights that CBD can potentially ameliorate certain psychiatric conditions, including schizophrenia, SUDs, and PTSD. However, more controlled studies and clinical trials, particularly investigating the mid- to long-term use of CBD, are required to conclusively establish its efficacy and safety in treating these conditions. The complex effects of CBD on neural activity patterns, likely by impacting the endocannabinoid system, warrant further research to reveal its therapeutic potential in psychiatry.

Plasma endocannabinoids in cocaine dependence and their relation to cerebral metabotropic glutamate receptor 5 density.

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N = 103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N = 92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N = 33; controls: N = 43). In an additional analysis using 11C-ABP688 positron emission tomography (PET) in a male subsample (CU: N = 18; controls: N = 16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence.

EMPOWERED trial: protocol for a randomised control trial of digitally supported, highly personalised and measurement-based care to improve functional outcomes in young people with mood disorders.

OBJECTIVES: Many adolescents and young adults with emerging mood disorders do not achieve substantial improvements in education, employment, or social function after receiving standard youth mental health care. We have developed a new model of care referred to as 'highly personalised and measurement-based care' (HP&MBC). HP&MBC involves repeated assessment of multidimensional domains of morbidity to enable continuous and personalised clinical decision-making. Although measurement-based care is common in medical disease management, it is not a standard practice in mental health. This clinical effectiveness trial tests whether HP&MBC, supported by continuous digital feedback, delivers better functional improvements than standard care and digital support. METHOD AND ANALYSIS: This controlled implementation trial is a PROBE study (Prospective, Randomised, Open, Blinded End-point) that comprises a multisite 24-month, assessor-blinded, follow-up study of 1500 individuals aged 15-25 years who present for mental health treatment. Eligible participants will be individually randomised (1:1) to 12 months of HP&MBC or standardised clinical care. The primary outcome measure is social and occupational functioning 12 months after trial entry, assessed by the Social and Occupational Functioning Assessment Scale. Clinical and social outcomes for all participants will be monitored for a further 12 months after cessation of active care. ETHICS AND DISSEMINATION: This clinical trial has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (HREC Approval Number: X22-0042 & 2022/ETH00725, Protocol ID: BMC-YMH-003-2018, protocol version: V.3, 03/08/2022). Research findings will be disseminated through peer-reviewed journals, presentations at scientific conferences, and to user and advocacy groups. Participant data will be deidentified. TRIAL REGISTRATION NUMBER: ACTRN12622000882729.

Cannabidiol enhances cerebral glucose utilization and ameliorates psychopathology and cognition: A case report in a clinically high-risk mental state.

Adolescent individuals often present with subtle, sub-threshold psychiatric syndromes that fluctuate or persist for years. These symptoms have been classified as Clinically High-Risk mental states (CHR), negatively affecting these individuals' psychosocial development and integration by reducing performance and affecting interpersonal relations. The pathophysiological underpinnings have not been studied in detail, contributing to the current lack of appropriate intervention strategies. This case report sheds new light on potential pathophysiological mechanisms of this condition, which may be addressed by novel treatment approaches such as cannabidiol. A 19-year-old student presented to our early intervention center with a marked cognitive decline within 6 months, anhedonia, ambivalence, social withdrawal, poverty of speech, and brief intermittent psychotic symptoms (delusions and hallucinations). He was diagnosed with CHR state, and we decided to treat him with the non-psychotomimetic phytocannabinoid cannabidiol. Cannabidiol is a promising compound carrying an orphan drug approval for rare certain childhood epilepsy types and is under investigation as an antipsychotic compound with a new mechanism of action compared to existing antipsychotics. We investigated the effect of oral cannabidiol (600 mg per day) over 4 weeks on psychopathology and cerebral glucose utilization. We observed no relevant side effects but a significant clinical improvement. In addition, positron emission tomography (PET) showed a considerable increase in cerebral [18F]fluoro-2-deoxyglucose (FDG) uptake in various brain regions. This finding suggests that cannabidiol may enhance cerebral glucose utilization, possibly via activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) by its endogenous ligand anandamide or related N-acylethanolamines. This mechanism may represent a new innovative treatment approach for CHR, especially given that many individuals with CHR and early psychosis do not substantially benefit from current psychopharmacological interventions.

Simultaneous Assessment of Serum Levels and Pharmacologic Effects of Cannabinoids on Endocannabinoids and N-Acylethanolamines by Liquid Chromatography-Tandem Mass Spectrometry.

Introduction: The primary compounds of Cannabis sativa, delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), inflict a direct influence on the endocannabinoid system-a complex lipid signaling network with a central role in neurotransmission and control of inhibitory and excitatory synapses. These phytocannabinoids often interact with endogenously produced endocannabinoids (eCBs), as well as their structurally related N-acylethanolamines (NAEs), to drive neurobiological, nociceptive, and inflammatory responses. Identifying and quantifying changes in these lipid neuromodulators can be challenging owing to their low abundance in complex matrices. Materials and Methods: This article describes a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the extraction and quantification of the eCBs anandamide and 2-arachidonoylglycerol, along with their congener NAEs oleoylethanolamine and palmitoylethanolamine, and phytocannabinoids CBD, Δ9-THC, and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol, a major metabolite of Δ9-THC. Our method was applied to explore pharmacokinetic and pharmacodynamic effects from intraperitoneal injections of Δ9-THC and CBD on circulating levels of eCBs and NAEs in rodent serum. Results: Detection limits ranged from low nanomolar to picomolar in concentration for eCBs (0.012-0.24 pmol/mL), NAEs (0.059 pmol/mL), and phytocannabinoids (0.24-0.73 pmol/mL). Our method displayed good linearity for calibration curves of all analytes (R2>0.99) as well as acceptable accuracy and precision, with quality controls not deviating >15% from their nominal value. Our LC-MS/MS method reliably identified changes to these endogenous lipid mediators that followed a causal relationship, which was dependent on both the type of phytocannabinoid administered and its pharmaceutical preparation. Conclusion: We present a rapid and reliable method for the simultaneous quantification of phytocannabinoids, eCBs, and NAEs in serum using LC-MS/MS. The accuracy and sensitivity of our assay infer it can routinely monitor endogenous levels of these lipid neuromodulators in serum and their response to external stimuli, including cannabimimetic agents.

Changing the Antipsychotic in Early Nonimprovers to Amisulpride or Olanzapine: Randomized, Double-Blind Trial in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Meta-analyses have shown that the majority of patients with schizophrenia who have not improved after 2 weeks of treatment with an antipsychotic drug are unlikely to fully respond later. We hypothesized that switching to another antipsychotic with a different receptor binding profile is an effective strategy in such a situation. STUDY DESIGN: In total, 327 inpatients with an acute exacerbation of schizophrenia were randomized to double-blind treatment with either olanzapine (5-20 mg/day) or amisulpride (200-800 mg/day). Those patients who had not reached at least 25% Positive-and-Negative-Syndrome-Scale (PANSS) total score reduction from baseline after 2 weeks (the "non-improvers") were rerandomized double-blind to either staying on the same compound ("stayers") or to switching to the other antipsychotic ("switchers") for another 6 weeks. The primary outcome was the difference in the number of patients in symptomatic remission between the combined "switchers" and the "stayers" after 8 weeks of treatment, analyzed by logistic regression. STUDY RESULTS: A total of 142 nonimprovers were rerandomized at week two. 25 (45.5 %) of the 'stayers' compared to 41 (68.3 %) of the "switchers" reached remission at endpoint (p = .006). Differences in secondary efficacy outcomes were not significant, except for the PANSS negative subscore and the Clinical-Global-Impression-Scale. "Switchers" and "stayers" did not differ in safety outcomes. CONCLUSIONS: Switching "non-improvers" from amisulpride to olanzapine or vice-versa increased remission rates and was safe. The superiority in the primary outcome was, however, not paralleled by significant differences in most secondary efficacy outcomes and the effect was only apparent at the last visit making replications of longer duration necessary.

Current State of Fluid Lipid Biomarkers for Personalized Diagnostics and Therapeutics in Schizophrenia Spectrum Disorders and Related Psychoses: A Narrative Review.

Schizophrenia spectrum disorders (SSD) are traditionally diagnosed and categorized through clinical assessment, owing to their complex heterogeneity and an insufficient understanding of their underlying pathology. However, disease progression and accurate clinical diagnosis become problematic when differentiating shared aspects amongst mental health conditions. Hence, there is a need for widely accessible biomarkers to identify and track the neurobiological and pathophysiological development of mental health conditions, including SSD. High-throughput omics applications involving the use of liquid chromatography-mass spectrometry (LC-MS) are driving a surge in biological data generation, providing systems-level insight into physiological and pathogenic conditions. Lipidomics is an emerging subset of metabolomics, largely underexplored amongst the omics systems. Lipid profiles in the brain are highly enriched with well-established functions, including maintenance, support, and signal transduction of neuronal signaling pathways, making them a prospective and exciting source of biological material for neuropsychiatric research. Importantly, changes in the lipid composition of the brain appear to extend into the periphery, as there is evidence that circulating lipid alterations correlate with alterations of psychiatric condition(s). The relative accessibility of fluid lipids offers a unique source to acquire a lipidomic "footprint" of molecular changes, which may support reliable diagnostics even at early disease stages, prediction of treatment response and monitoring of treatment success (theranostics). Here, we summarize the latest fluid lipidomics discoveries in SSD-related research, examining the latest strategies to integrate information into multi-systems overviews that generate new perspectives of SSD-related psychosis identification, development, and treatment.

Effects of adjunctive brexpiprazole on sleep-wake and circadian parameters in youth with depressive disorders: study protocol for a clinical trial.

INTRODUCTION: Sleep-wake and circadian disturbance is a key feature of mood disorders with a potential causal role and particular relevance to young people. Brexpiprazole is a second-generation antipsychotic medication with demonstrated efficacy as an adjunct to antidepressant treatment for major depressive disorder (MDD) in adults, with preliminary evidence suggesting greater effectiveness in subgroups of depressed patients with sleep disturbances. This clinical trial aims to evaluate the relationships between changes in sleep-wake and circadian parameters and changes in depressive symptoms following adjunctive brexpiprazole treatment in young adults with MDD and sleep-wake disturbance. METHODS AND ANALYSIS: This study is designed as a 16 week (8 weeks active treatment, 8 weeks follow-up) mechanistic, open-label, single-arm, phase IV clinical trial and aims to recruit 50 young people aged 18-30 with MDD and sleep-wake cycle disturbance through an early intervention youth mental health clinic in Sydney, Australia. At baseline, participants will undergo multidimensional outcome assessment and subsequently receive 8 weeks of open-label treatment with brexpiprazole as adjunctive to their stable psychotropic medication. Following 4 weeks of treatment, clinical and self-report measures will be repeated. Ambulatory sleep-wake monitoring will be conducted continuously for the duration of treatment. After 8 weeks of treatment, all multidimensional outcome assessments will be repeated. Follow-up visits will be conducted 4 and 8 weeks after trial completion (including sleep-wake, clinical and self-report assessments). Circadian rhythm biomarkers including salivary melatonin, cortisol and core body temperature will be collected during an in-lab assessment. Additionally, metabolic, inflammatory and genetic risk markers will be collected at baseline and after 8 weeks of treatment. ETHICS AND DISSEMINATION: This trial protocol has been approved by the Human Research Ethics Committee of the Sydney Local Health District (X19-0417 and 2019/ETH12986, Protocol Version 1-3, dated 25 February 2021). The results of this study, in deidentified form, will be disseminated through publication in peer-reviewed journals, scholarly book chapters, presentation at conferences and publication in conference proceedings. TRIAL REGISTRATION NUMBER: ACTRN12619001456145.

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function.

Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress.

Case Report: Severe Adolescent Major Depressive Syndrome Turns Out to Be an Unusual Case of Anti-NMDA Receptor Encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neuroinflammatory condition mediated by autoantibodies against the GluN1 subunit of the receptor. Clinically, it is characterized by a complex neuropsychiatric presentation with rapidly progressive psychiatric symptoms, cognitive deficits, seizures, and abnormal movements. Isolated psychiatric manifestations of anti-NMDAR encephalitis are rare and usually dominated by psychotic symptoms. We present a case of an 18-year-old female high school student-without a previous history of psychiatric disorders-with a rapid onset severe depressive syndrome. Surprisingly, we found pleocytosis and anti-NMDAR autoantibodies in the cerebrospinal fluid (CSF), despite an otherwise unremarkable diagnostic workup, including blood test, clinical examination, and cranial magnetic resonance imaging (MRI). After intravenous immunoglobulins treatment, a complete remission of the initial symptoms was observed. In a follow-up 5 years later, the young woman did not experience any relapse or sequelae. Anti-NMDAR encephalitis can present in rare cases as an organic disorder with major depressive symptoms without distinct concomitant psychotic or neurological symptoms. A clinical presentation such as a rapid onset of symptoms, distinct disturbance in the thought process, restlessness, and cognitive deficits should prompt screening for NMDAR- and other neural autoantibodies to rule out this rare but debilitating pathology.

Neurobiology Youth Follow-up Study: protocol to establish a longitudinal and prospective research database using multimodal assessments for current and past mental health treatment-seeking young people within an early intervention service.

INTRODUCTION: Approximately 75% of major mental illness occurs before the age of 25 years. Despite this, our capacity to provide effective, early and personalised interventions is limited by insufficient evidence for characterising early-stage, and less specific, presentations of major mental disorders in youth populations. This article describes the protocol for setting up a large-scale database that will collect longitudinal, prospective data that incorporate clinical, social and occupational function, neuropsychological, circadian, metabolic, family history and genetic metrics. By collecting data in a research-purposed, standardised manner, the 'Neurobiology Youth Follow-up Study' should improve identification, characterisation and profiling of youth attending mental healthcare, to better inform diagnosis and treatment at critical time points. The overall goal is enhanced long-term clinical and functional outcomes. METHODS AND ANALYSIS: This longitudinal clinical cohort study will invite participation from youth (12-30 years) who seek help for mental health-related issues at an early intervention service (headspace Camperdown) and linked services. Participants will be prospectively tracked over 3 years with a series of standardised multimodal assessments at baseline, 6, 12, 24 and 36 months. Evaluations will include: (1) clinician-administered and self-report assessments determining clinical stage, pathophysiological pathways to illness, diagnosis, symptomatology, social and occupational function; (2) neuropsychological profile; (3) sleep-wake patterns and circadian rhythms; (4) metabolic markers and (5) genetics. These data will be used to: (1) model the impact of demographic, phenomenological and treatment variables, on clinical and functional outcomes; (2) map neurobiological profiles and changes onto a transdiagnostic clinical stage and pathophysiological mechanisms framework. ETHICS AND DISSEMINATION: This study protocol has been approved by the Human Research Ethics Committee of the Sydney Local Health District (2020/ETH01272, protocol V.1.3, 14 October 2020). Research findings will be disseminated through peer-reviewed journals and presentations at scientific conferences and to user and advocacy groups. Participant data will be de-identified.

Cannabidiol and Amisulpride Improve Cognition in Acute Schizophrenia in an Explorative, Double-Blind, Active-Controlled, Randomized Clinical Trial.

Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic properties in recent clinical trials. While it has also been suggested a promising candidate for the treatment of neurodegenerative disorders, it failed to demonstrate efficacy in cognitive impairments associated with schizophrenia as an add-on treatment (600 mg/day for 6 weeks) in 18 chronically ill patients co-treated with a variety of psychopharmacologic drugs. Here, we report on the results of parallel-group, active-controlled, mono-therapeutic, double-blind, randomized clinical trial (CBD-CT1; ClinicalTrials.gov identifier: NCT00628290) in 42 acute paranoid schizophrenic patients receiving either CBD (up to 800 mg/day) or amisulpride (AMI, up to 800 mg/day) for four weeks in an inpatient setting with neurocognition as a secondary objective. Twentynine patients (15 and 14 in the CBD and AMI group, respectively) completed two cognitive assessments at baseline and the end of the treatment period. We investigated the following cognitive domains: pattern recognition, attention, working memory, verbal and visual memory and learning, processing speed, and verbal executive functions. When applying the Bonferroni correction for multiple testing, p < 0.0004 would indicate statistical significance. There was no relevant difference in neurocognitive performance between the CBD and the AMI group at baseline, and we observed no post-treatment differences between both groups. However, we observed improvements within both groups from pre-to post-treatment (standardized differences reported as Cohen's d) in visual memory (CBD: 0.49, p = 0.015 vs. AMI: 0.63, p = 0.018) and processing speed (CBD: 0.41, p = 0.004 vs. AMI: 0.57, p = 0.023). Furthermore, CBD improved sustained attention (CBD: 0.47, p = 0.013, vs. AMI: 0.52, p = 0.085), and visuomotor coordination (CBD: 0.32, p = 0.010 vs. AMI: 0.63, p = 0.088) while AMI led to enhanced working memory performance in two different paradigms (Subject Ordered Pointing Task-AMI: 0.53, p = 0.043 vs. CBD: 0.03, p = 0.932 and Letter Number Sequencing-AMI: 0.67, p = 0.017 vs. CBD: 0.08 p = 0.755). There was no relevant correlation between changes in neurocognitive parameters and psychotic symptoms or anandamide serum levels. This study shows that both CBD and AMI improve neurocognitive functioning with comparable efficacy in young and acutely ill schizophrenia patients via an anandamide-independent mechanism.

Neural Autoantibodies in Cerebrospinal Fluid and Serum in Clinical High Risk for Psychosis, First-Episode Psychosis, and Healthy Volunteers.

The pathophysiological role of neural autoantibodies in acute psychotic disorders is receiving increased attention. However, there is still an ongoing debate, whether predominantly psychotic manifestations of autoimmune encephalitides exist that may remain undetected and, thus, untreated. Furthermore, it is discussed if such conditions can be diagnosed based on serum antibody results or if a reliable diagnosis requires additional cerebrospinal fluids (CSF) results. In this study, we screened pairs of serum and CSF samples from antipsychotic-naïve individuals with first-episode schizophrenic psychosis (FEP, n = 103), clinical high risk for psychosis (CHR, n = 47), and healthy volunteers (HV, n = 40) for eight different antibodies against various antigens that have been shown to be associated with autoimmune encephalitides: N-methyl-D-aspartate receptor (NMDAR, NR1 subunits only), glutamic acid decarboxylase (GAD65), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 protein (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit 1, AMPAR subunit 2, γ-aminobutyric acid-B receptors (GABABR), and glycine receptors. All patients were within the norm with regards to a careful neurological examination, a magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG), and routine blood pathology. All CSF samples were autoantibody-negative. In three serum samples of individuals with FEP, we detected low-titer CASPR2 immunoglobulin (Ig) G antibodies (≤1:160, n = 2) and non-IgG antibodies against NMDAR (n = 1) (overall serum-autoantibody prevalence in FEP: 2.91%). However, the IgG titers were below the laboratory cut-off defined for positivity, and non-IgG antibodies are of no clinical relevance. This suggests that there were no cases of autoimmune encephalitis in our cohort. Our results highlight the importance and the high specificity of CSF analysis to reliably detect autoantibodies. They confirm the hypothesis that pure psychotic manifestations of antibody-associated autoimmune encephalitides without any additional neuropsychiatric findings are very rare. However, special attention must be paid to those presenting with atypical mental illnesses with additional neurological symptoms, evidence of clinically-significant cognitive involvement, profound sleep-wake perturbations, seizures, electroencephalographic, or magnetic resonance imaging pathologies to be able to identify cases with autoimmune-mediated psychiatric syndromes.

Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Emotion, Cognition, and Attention: A Double-Blind, Placebo-Controlled, Randomized Experimental Trial in Healthy Volunteers.

The two main phytocannabinoids-delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)-have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; ClinicalTrials.gov identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories-more precisely, the performance-related activity and extraversion-, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances.

Youth Mental Health Tracker: protocol to establish a longitudinal cohort and research database for young people attending Australian mental health services.

INTRODUCTION: Mental disorders are a leading cause of long-term disability worldwide. Much of the burden of mental ill-health is mediated by early onset, comorbidities with physical health conditions and chronicity of the illnesses. This study aims to track the early period of mental disorders among young people presenting to Australian mental health services to facilitate more streamlined transdiagnostic processes, highly personalised and measurement-based care, secondary prevention and enhanced long-term outcomes. METHODS AND ANALYSIS: Recruitment to this large-scale, multisite, prospective, transdiagnostic, longitudinal clinical cohort study ('Youth Mental Health Tracker') will be offered to all young people between the ages of 12 and 30 years presenting to participating services with proficiency in English and no history of intellectual disability. Young people will be tracked over 3 years with standardised assessments at baseline and 3, 6, 12, 24 and 36 months. Assessments will include self-report and clinician-administered measures, covering five key domains including: (1) social and occupational function; (2) self-harm, suicidal thoughts and behaviour; (3) alcohol or other substance misuse; (4) physical health; and (5) illness type, clinical stage and trajectory. Data collection will be facilitated by the use of health information technology. The data will be used to: (1) determine prospectively the course of multidimensional functional outcomes, based on the differential impact of demographics, medication, psychological interventions and other key potentially modifiable moderator variables and (2) map pathophysiological mechanisms and clinical illness trajectories to determine transition rates of young people to more severe illness forms. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (2019/ETH00469). All data will be non-identifiable, and research findings will be disseminated through peer-reviewed journals and scientific conference presentations.

Chronic Psychosocial Stress Causes Increased Anxiety-Like Behavior and Alters Endocannabinoid Levels in the Brain of C57Bl/6J Mice.

Introduction: Chronic stress causes a variety of physiological and behavioral alterations, including social impairments, altered endocrine function, and an increased risk for psychiatric disorders. Thereby, social stress is one of the most effective stressful stimuli among mammals and considered to be one of the major risk factors for the onset and progression of neuropsychiatric diseases. For analyzing the effects of social stress in mice, the resident/intruder paradigm of social defeat is a widely used model. Although the chronic social defeat stress model has been extensively studied, little is known about the effects of repeated or chronic social defeat stress on the endocannabinoid system (ECS). The present study aimed to understand the effects of chronic social stress on anxiety behavior and the levels of endocannabinoids (ECs) and two N-acylethanolamines (NAEs) in different brain regions of mice. Materials and Methods: Two-month-old, male C57Bl/6J mice were exposed to chronic psychosocial stress for 3 weeks. The effects of stress on anxiety behavior were measured using the light-dark box and hole board test. The EC levels of 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoylethanolamine [AEA]), as well as the levels of two NAEs (oleoylethanolamide [OEA] and palmitoylethanolamide), were analyzed by liquid chromatography-tandem mass spectrometry in the hippocampus, cerebellum, and cortex. Results: In comparison with control mice (n=12), mice exposed to social defeat stress (n=11) showed increased anxiety behaviors in the light-dark box and hole board test and gained significantly more weight during the experimental period. Additionally, chronic social stress induced differential alterations in the brain levels of 2-AG and AEA. More precisely, 2-AG levels were higher in the cortex and cerebellum, whereas reduced AEA levels were found in the hippocampus. Furthermore, we observed lower OEA levels in the hippocampus. Conclusion: The current study confirms that the ECS plays an essential role in stress responses, whereby its modulation seems to be brain region dependent.